U.S. patent application number 10/387543 was filed with the patent office on 2004-01-15 for pyrimidine derivatives and new pyridine derivatives.
This patent application is currently assigned to AJINOMOTO CO., INC.. Invention is credited to Fujita, Shinichi, Hagihara, Masako, Iwayama, Satoshi, Koganei, Hajime, Niwa, Seiji, Ohno, Seiji, Okajima, Akiko, Ono, Yukitsugu, Otani, Kayo, Takahara, Akira, Takeda, Tomoko.
Application Number | 20040009991 10/387543 |
Document ID | / |
Family ID | 26600030 |
Filed Date | 2004-01-15 |
United States Patent
Application |
20040009991 |
Kind Code |
A1 |
Ohno, Seiji ; et
al. |
January 15, 2004 |
Pyrimidine derivatives and new pyridine derivatives
Abstract
Achirai pyrimidine derivatives and pyridine derivatives of the
following formulae or analogs thereof have selective N-type calcium
channel antagonistic activity and showed analgesic action when they
were taken orally. They are useful as therapeutic agents for pains
and various diseases associated with the N-type calcium channels.
1
Inventors: |
Ohno, Seiji; (Kawasaki-Shi,
JP) ; Otani, Kayo; (Kawasaki-Shi, JP) ; Niwa,
Seiji; (Kawasaki-Shi, JP) ; Iwayama, Satoshi;
(Kawasaki-Shi, JP) ; Takahara, Akira;
(Kawasaki-Shi, JP) ; Koganei, Hajime;
(Kawasaki-Shi, JP) ; Ono, Yukitsugu;
(Kawasaki-Shi, JP) ; Fujita, Shinichi;
(Kawasaki-Shi, JP) ; Takeda, Tomoko;
(Kawasaki-Shi, JP) ; Hagihara, Masako;
(Kawasaki-Shi, JP) ; Okajima, Akiko;
(Kawasaki-Shi, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
AJINOMOTO CO., INC.
Tokyo
JP
|
Family ID: |
26600030 |
Appl. No.: |
10/387543 |
Filed: |
March 14, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10387543 |
Mar 14, 2003 |
|
|
|
PCT/JP01/07841 |
Sep 10, 2001 |
|
|
|
Current U.S.
Class: |
514/256 ;
514/275; 544/331; 544/333; 544/335 |
Current CPC
Class: |
C07D 239/42 20130101;
C07D 401/04 20130101; C07D 403/04 20130101; A61P 25/00 20180101;
A61K 31/455 20130101; C07D 239/28 20130101; A61P 9/10 20180101;
A61P 43/00 20180101; C07D 213/82 20130101; A61P 11/06 20180101;
A61K 31/496 20130101; A61K 31/506 20130101; A61K 31/5377 20130101;
A61K 31/551 20130101; A61P 1/04 20180101; C07D 239/38 20130101;
A61K 31/55 20130101; A61P 1/00 20180101; C07D 213/80 20130101; C07D
417/04 20130101; A61P 25/06 20180101; A61P 25/04 20180101; A61P
25/28 20180101; C07D 239/34 20130101; A61P 25/16 20180101; A61P
9/00 20180101; A61P 25/30 20180101; A61P 29/00 20180101; C07D
409/04 20130101; A61K 31/505 20130101 |
Class at
Publication: |
514/256 ;
514/275; 544/331; 544/333; 544/335 |
International
Class: |
A61K 031/505; A61K
031/506; C07D 49/02; C07D 45/02; C07D 43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 14, 2000 |
JP |
2000-280438 |
Apr 25, 2001 |
JP |
2001-126832 |
Claims
What is claimed is;
1. Pyrimidine derivatives of the following general formula (1), and
pharmaceutically acceptable salts thereof: 183wherein A represents
a group of the following general formula (2), or 1-naphthyl,
2-naphthyl, indole-2-yl, indole-3-yl, thiophene-3-yl,
thiophene-2-yl, furan-3-yl, furan-2-yl, pyridine-4-yl,
pyridine-3-yl or pyridine-2-yl group: 184wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 may be the same or different from each
other and each represent hydrogen atom, a halogen atom, hydroxyl
group, carboxyl group, amino group, cyano group, nitro group, a
lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a
lower alkynyl group, a lower alkylamino group, a lower alkylthio
group, a lower alkanoyl group, a lower alkoxycarbonyl group, a
hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a
hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an
aryl-lower alkoxyl group or an aroyl group, C represents a hydrogen
atom, a lower alkyl group, a lower alkylamino group, a lower
alkylthio group, a lower alkyl sulfinyl group, a lower alkyl
sulfonyl group, a lower alkoxyl group, a hydroxy-lower alkyl group,
a hydroxy-lower alkylamino group, a hydroxy-lower alkylthio group,
a hydroxy-lower alkoxyl group, an amino-lower alkyl group, an
amino-lower alkylamino group, an amino-lower alkylthio group, an
amino-lower alkoxyl group, an aryl-lower alkyl group, an aryl-lower
alkylamino group, an aryl-lower alkylthio group, an aryl-lower
alkoxyl group, a heteroaryl-lower alkyl group, a heteroaryl-lower
alkylamino group, a heteroaryl-lower alkylthio group, a
heteroaryl-lower alkoxyl group, a halogeno-lower alkyl group, a
halogeno-lower alkylamino group, a halogeno-lower alkylthio group,
a halogeno-lower alkoxyl group, a substituted or unsubstituted aryl
group, a substituted or unsubstituted heteroaryl group, a
substituted or unsubstituted cyclic alkyl group, a lower alkyl
group substituted with a substituted or unsubstituted cyclic alkyl
group, a substituted or unsubstituted aryloxy group or a
substituted or unsubstituted heteroaryloxy group, E represents a
hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano
group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group, a
hydroxy-lower alkyl group, an amino-lower alkyl group, a
halogeno-lower alkyl group, a substituted or unsubstituted aryl
group, a substituted or unsubstituted heteroaryl group or a group
of the following general formula (3) or (4): 185wherein X.sub.2
represents O, S or N--R.sub.8, n represents an integer of 1 to 6, K
in general formula (3) represents a hydrogen atom, a halogen atom,
hydroxyl group, carboxyl group, amino group, cyano group, nitro
group or azido group, G in the general formula (4) represents N or
C--H, wherein R.sup.6 to R.sup.8 may be the same or different from
each other, and each represents a hydrogen atom, a linear, branched
or cyclic, saturated or unsaturated hydrocarbon group having 1 to 6
carbon atoms, a substituted or unsubstituted aryl group, a
substituted or unsubstituted heteroaryl group, a hydroxy-lower
alkyl group, a hydroxy-lower alkenyl group, an amino-lower alkyl
group, an amino-lower alkenyl group, a halogeno-lower alkyl group,
a halogeno-lower alkenyl group, an aryl-lower alkyl group, an
aryl-lower alkenyl group, a heteroaryl-lower alkyl group, a
heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a
cyano-lower alkenyl group, and the chains may contain a hetero
atom, or R.sup.6 and R.sup.7 may together form a ring which may
contain a hetero atom, F represents a group of the following
general formula (5), or thiophene-3-yl, thiophene-2-yl, furan-3-yl,
furan-2-yl, pyridine-4-yl, pyridine-3-yl, pyridine-2-yl,
cyclopentyl group, cyclohexyl group, morpholine-1-yl,
imidazole-1-yl, pyrrolidine-1-yl, pyrrolidinone-1-yl,
piperidine-1-yl, piperidinone-1-yl or piperazine-1-yl group:
186wherein R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 may
be the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkylamino group, a lower alkylthio group, a lower alkanoyl
group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group,
a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an
aryl-lower alkyl group, an aryl-lower alkoxyl group, a lower
alkoxycarbonyl group, an aroyl group, a substituted or
unsubstituted aryl group, a substituted or unsubstituted heteroaryl
group or a saturated cyclic hydrocarbon group having 3 to 8 carbon
atoms, which may contain a hetero atom in the chain thereof and/or
the ring thereof, X.sub.1 represents >N--R.sup.14 wherein
R.sup.14 represents a hydrogen atom, a lower alkyl group which may
contain a hetero atom in the chain thereof, a hydroxy-lower alkyl
group, an amino-lower alkyl group, a carboxy-lower alkyl group or a
lower alkyloxycarbonyl-lower alkyl group, Y represents a saturated
or unsaturated linear hydrocarbon group having 1 to 6 carbon atoms,
which may contain a hetero atom in the group thereof, or a group of
the following general formula (6): 187wherein R.sub.15 represents a
hydrogen atom, a substituted or unsubstituted, saturated or
unsaturated linear, branched or cyclic hydrocarbon group having 1
to 6 carbon atoms, a substituted or unsubstituted aryl group, a
substituted or unsubstituted heteroaryl group, a hydroxy-lower
alkyl group, a hydroxy-lower alkenyl group, an amino-lower alkyl
group, an amino-lower alkenyl group, a halogeno-lower alkyl group,
a halogeno-lower alkenyl group, an aryl-lower alkyl group, an
aryl-lower alkenyl group, a heteroaryl-lower alkyl group, a
heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a
cyano-lower alkenyl group, and the chains of R.sup.15 may contain a
hetero atom, and m represents an integer of 0 to 5.
2. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 1, wherein F represents a group of
the general formula (5), thiophene-3-yl, thiophene-2-yl, furan-3-yl
or furan-2-yl group, Y represents a saturated or unsaturated linear
hydrocarbon group having 2 to 6 carbon atoms, which may contain a
hetero atom in the group thereof, or a group of the general formula
(6) and m is an integer of 1 to 5.
3. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 1, wherein A represents a group of
the general formula (2), F represents a group of the general
formula (5), and X.sub.1 represents >N--R.sup.14 wherein
R.sup.14 represents a hydrogen atom.
4. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 1, wherein A represents a group of
the general formula (2), C represents a lower alkyl group, F
represents a group of the general formula (5), X.sub.1 represents
>N--R.sup.14 wherein R.sup.14 represents a hydrogen atom, and Y
represents a saturated or unsaturated hydrocarbon group having 3
carbon atoms.
5. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 1, wherein A represents a group of
the general formula (2), C represents a lower alkylthio group, a
lower alkyl sulfinyl group or a lower alkyl sulfonyl group, F
represents a group of the general formula (5), X.sub.1 represents
>N--R.sup.14 wherein R.sup.14 represents a hydrogen atom, and Y
represents a saturated or unsaturated hydrocarbon group having 3
carbon atoms.
6. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 1, wherein A represents a group of
the general formula (2), C represents a lower alkyl group, E
represents a methyl group, F represents a group of the general
formula (5), X.sub.1 represents >N--R.sup.14 wherein R.sup.14
represents a hydrogen atom, and Y represents a saturated or
unsaturated hydrocarbon group having 3 carbon atoms.
7. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 1, wherein A represents a group of
the general formula (2), C represents a lower alkylthio group, E
represents a methyl group, F represents a group of the general
formula (5), X.sub.1 represents >N--R.sup.14 wherein R.sup.14
represents a hydrogen atom, and Y represents a saturated or
unsaturated hydrocarbon group having 3 carbon atoms.
8. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 1, wherein C represents a hydrogen
atom, a lower alkyl group which may contain a hetero atom in the
chain thereof, a lower alkylamino group, a lower alkylthio group, a
lower alkoxyl group, a hydroxy-lower alkyl group, a hydroxy-lower
alkylamino group, a hydroxy-lower alkylthio group, a hydroxy-lower
alkoxyl group, an amino-lower alkyl group, an amino-lower
alkylamino group, an amino-lower alkylthio group, an amino-lower
alkoxyl group, an aryl-lower alkyl group which may contain a hetero
atom in the chain thereof, an aryl-lower alkylamino group, an
aryl-lower alkylthio group, an aryl-lower alkoxyl group, a
heteroaryl-lower alkyl group, a heteroaryl-lower alkylamino group,
a heteroaryl-lower alkylthio group, a heteroaryl-lower alkoxyl
group, a halogeno-lower alkyl group, a halogeno-lower alkylamino
group, a halogeno-lower alkylthio group, a halogeno-lower alkoxyl
group, a substituted or unsubstituted aryl group, or a substituted
or unsubstituted heteroaryl group.
9. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 8, wherein A represents a group of
the general formula (2), C represents a lower-alkyl group or a
lower-alkylthio group, F represents a group of the general formula
(5), X.sub.1 represents >N--R.sup.14 wherein R.sup.14 represents
a hydrogen atom, and Y represents a saturated or unsaturated
hydrocarbon group having 3 to 4 carbon atoms.
10. Pyrimidine derivatives of the following general formula (1'),
and pharmaceutically acceptable salts thereof: 188wherein A
represents a group of the following general formula (2), or
1-naphthyl, 2-naphthyl, indole-2-yl, indole-3-yl, thiophene-3-yl,
thiophene-2-yl, furan-3-yl, furan-2-yl, pyridine-4-yl,
pyridine-3-yl or pyridine-2-yl group: 189wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4 and R.sup.5 may be the same or different from each
other and each represents a hydrogen atom, a halogen atom, hydroxyl
group, carboxyl group, amino group, cyano group, nitro group, a
lower alkyl group, a lower alkoxyl group, a lower alkenyl group, a
lower alkynyl group, a lower alkylamino group, a lower alkylthio
group, a lower alkanoyl group, a lower alkoxycarbonyl group, a
hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group, a
hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an
aryl-lower alkoxyl group or an aroyl group, C represents a hydrogen
atom, a lower alkyl group, a lower alkylamino group, a lower
alkylthio group, a lower alkyl sulfinyl group, a lower alkyl
sulfonyl group, a lower alkoxyl group, a hydroxy-lower alkyl group,
a hydroxy-lower alkylamino group, a hydroxy-lower alkylthio group,
a hydroxy-lower alkoxyl group, an amino-lower alkyl group, an
amino-lower alkylamino group, an amino-lower alkylthio group, an
amino-lower alkoxyl group, an aryl-lower alkyl group, an aryl-lower
alkylamino group, an aryl-lower alkylthio group, an aryl-lower
alkoxyl group, a heteroaryl-lower alkyl group, a heteroaryl-lower
alkylamino group, a heteroaryl-lower alkylthio group, a
heteroaryl-lower alkoxyl group, a halogeno-lower alkyl group, a
halogeno-lower alkylamino group, a halogeno-lower alkylthio group,
a halogeno-lower alkoxyl group, a substituted or unsubstituted aryl
group, a substituted or unsubstituted heteroaryl group, a
substituted or unsubstituted cyclic alkyl group, a lower alkyl
group substituted with a substituted or unsubstituted cyclic alkyl
group, a substituted or unsubstituted aryloxy group or a
substituted or unsubstituted heteroaryloxy group, E represents a
hydrogen atom, a lower alkyl group, dimethoxymethyl group, cyano
group, an aryl-lower alkyl group, a heteroaryl-lower alkyl group, a
hydroxy-lower alkyl group, an amino-lower alkyl group, a
halogeno-lower alkyl group, a substituted or unsubstituted aryl
group, a substituted or unsubstituted heteroaryl group or a group
of the following general formula (3) or (4): 190wherein X.sub.2
represents O, S or N--R.sub.8, n represents an integer of 1 to 6, K
in general formula (3) represents a hydrogen atom, a halogen atom,
hydroxyl group, carboxyl group, amino group, cyano group, nitro
group or azido group, G in the general formula (4) represents N or
C--H, wherein R.sup.6 to R.sup.8 may be the same or different from
each other, and each represents a hydrogen atom, a linear, branched
or cyclic, saturated or unsaturated hydrocarbon group having 1 to 6
carbon atoms, a substituted or unsubstituted aryl group, a
substituted or unsubstituted heteroaryl group, a hydroxy-lower
alkyl group, a hydroxy-lower alkenyl group, an amino-lower alkyl
group, an amino-lower alkenyl group, a halogeno-lower alkyl group,
a halogeno-lower alkenyl group, an aryl-lower alkyl group, an
aryl-lower alkenyl group, a heteroaryl-lower alkyl group, a
heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a
cyano-lower alkenyl group, and the chains may contain a hetero
atom, or R.sup.6 and R.sup.7 may together form a ring which may
contain a hetero atom, F represents a group of the following
general formula (5), thiophene-3-yl, thiophene-2-yl, furan-3-yl,
furan-2-yl, pyridine-4-yl, pyridine-3-yl or pyridine-2-yl group,
cyclopentyl group, cyclohexyl group, morpholine-1-yl,
imidazole-1-yl, pyrrolidine-1-yl, pyrrolidinone-1-yl,
piperidine-1-yl, piperidinone-1-yl or piperazine-1-yl group:
191wherein R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13 may
be the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkylamino group, a lower alkylthio group, a lower alkanoyl
group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group,
a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an
aryl-lower alkyl group, an aryl-lower alkoxyl group, a lower
alkoxycarbonyl group, an aroyl group, a substituted or
unsubstituted aryl group, a substituted or unsubstituted heteroaryl
group or a saturated cyclic hydrocarbon group having 3 to 8 carbon
atoms, which may contain a hetero atom in the chain thereof and/or
the ring thereof, X.sub.3 represents a group of the following
general formula (7) or (8): 192Y represents a saturated or
unsaturated linear hydrocarbon group having 2 to 6 carbon atoms,
which may contain a hetero atom in the group thereof, or a group of
the following general formula (6): 193wherein R.sub.15 represents a
hydrogen atom, a substituted or unsubstituted, saturated or
unsaturated linear, branched or cyclic hydrocarbon group having 1
to 6 carbon atoms, a substituted or unsubstituted aryl group, a
substituted or unsubstituted heteroaryl group, a hydroxy-lower
alkyl group, a hydroxy-lower alkenyl group, an amino-lower alkyl
group, an amino-lower alkenyl group, a halogeno-lower alkyl group,
a halogeno-lower alkenyl group, an aryl-lower alkyl group, an
aryl-lower alkenyl group, a heteroaryl-lower alkyl group, a
heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a
cyano-lower alkenyl group, and the chains of R.sup.15 may contain a
hetero atom, and m represents an integer of 1 to 5.
11. The pyrimidine derivatives, and pharmaceutically acceptable
salts thereof according to claim 10, wherein A represents a group
of the general formula (2), F represents a group of the general
formula (5), X.sub.3 represents a group of the general formula (7)
or (8) and Y represents a group of the general formula (6) wherein
m represents an integer of 1 to 4 and R.sup.15 represents a
substituted or unsubstituted aryl group, or a saturated or
unsaturated hydrocarbon group having 2 to 4 carbon atoms.
12. Pyridine derivatives of the following general formula (1"), and
pharmaceutically acceptable salts thereof: 194wherein A' represents
a group of the following general formula (9): 195wherein R.sup.16,
R.sup.17, R.sup.18, R.sup.19 and R.sup.20 may be the same or
different from each other and each represents a hydrogen atom, a
halogen atom, hydroxyl group, carboxyl group, amino group, cyano
group, nitro group, a lower alkyl group, a lower alkoxyl group or a
lower alkylamino group, C' and E' may be the same or different from
each other and each represents a hydrogen atom, a lower alkyl group
which may contain a hetero atom in the chain thereof,
dimethoxymethyl group, cyano group, an aryl-lower alkyl group, a
heteroaryl-lower alkyl group, a hydroxy-lower alkyl group, an
amino-lower alkyl group, a halogeno-lower alkyl group, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group or a group of the following general
formula (3) or (4): 196wherein X.sub.2 represents O, S or
N--R.sub.8, n represents an integer of 1 to 6, K in general formula
(3) represents a hydrogen atom, a halogen atom, hydroxyl group,
carboxyl group, amino group, cyano group, nitro group, azido group,
a substituted or unsubstituted aryl group or a substituted or
unsubstituted heteroaryl group, G in the general formula (4)
represents N or C--H, wherein R.sup.6 to R.sup.8 may be the same or
different from each other, and each represents a hydrogen atom, a
linear, branched or cyclic, saturated or unsaturated hydrocarbon
group having 1 to 6 carbon atoms, a substituted or unsubstituted
aryl group, a substituted or unsubstituted heteroaryl group, a
hydroxy-lower alkyl group, a hydroxy-lower alkenyl group, an
amino-lower alkyl group, an amino-lower alkenyl group, a
halogeno-lower alkyl group, a halogeno-lower alkenyl group, an
aryl-lower alkyl group, an aryl-lower alkenyl group, a
heteroaryl-lower alkyl group, a heteroaryl-lower alkenyl group, a
cyano-lower alkyl group or a cyano-lower alkenyl group, and the
chains may contain a hetero atom, or R.sup.6 and R.sup.7may
together form a ring which may contain a hetero atom, B' represents
a hydrogen atom only when Y' represents the general formula (12)
and R.sup.26 is a substituted or unsubstituted aryl group, a
carboxyl group only when Y' represents the general formula (12) or
Y' and F' together form the following general formula (12'-1),
(12'-2), (12"-1) or (12"-2), or a group of the following general
formula (10): 197wherein Z represents a nitrogen atom, an oxygen
atom or a carbon atom, p represents an integer of 1 to 3, J
represents an unsubstituted group only when Z is an oxygen atom, a
hydrogen atom, a lower alkyl group which may contain a hetero atom
in the group thereof, a hydroxy-lower alkyl group, an amino-lower
alkyl group, a substituted or unsubstituted aryl group, a
substituted or unsubstituted heteroaryl group, a substituted or
unsubstituted aryl-lower alkyl group or a substituted or
unsubstituted heteroaryl-lower alkyl group, F' represents the
following general formula (11): 198wherein R.sup.21, R.sup.22,
R.sup.23, R.sup.24 and R.sup.25 may be the same or different from
each other and each represents a hydrogen atom, a halogen atom,
hydroxyl group, carboxyl group, amino group, cyano group, nitro
group, a lower alkyl group, a lower alkoxyl group, a lower
alkylamino group, a substituted or unsubstituted aryl group or a
substituted or unsubstituted heteroaryl group, X' represents an
oxygen atom or >NH, Y' represents a saturated or unsaturated
linear hydrocarbon group having 1 to 6 carbon atoms, which may
contain a hetero atom in the group thereof, or a group of the
following general formula (12): 199wherein R.sup.26 represents a
substituted or unsubstituted aryl group or a substituted or
unsubstituted heteroaryl group and h represents an integer of 0 to
5, Y' and F' together form a group of the following general formula
(12'-1), (12'-2), (12"-1) or (12"-2): 200wherein h represents an
integer of 0 to 5, i represents an integer of 2 to 5, R.sup.32,
R.sup.33, R.sup.34 and R.sup.35 may be the same or different from
each other and each represents a hydrogen atom, a halogen atom,
hydroxyl group, carboxyl group, amino group, cyano group, nitro
group, a lower alkyl group, a lower alkoxyl group, a lower
alkylamino group, a substituted or unsubstituted aryl group or a
substituted or unsubstituted heteroaryl group.
13. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 12, excluding the case wherein Y' and F'
together form a group of the general formula (12'-1), (12'-2),
(12"-1) or (12"-2).
14. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 13, wherein B' represents a group of the
general formula (10).
15. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 13, wherein B' represents a group of the
general formula (10), Y' represents a group of the general formula
(12), and X' represents an oxygen atom.
16. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 13, wherein B' represents carboxyl
groups, and E' represents a group of the general formula (3) or
(4).
17. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 13, wherein B' represents carboxyl
groups, E' represents a group of the general formula (3) or (4), X'
represents an oxygen atom, and Y' represents a group of the general
formula (12).
18. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 13, wherein C' and E' may be the same or
different from each other and each represents a hydrogen atom, a
lower alkyl group which may contain a hetero atom in the chain
thereof, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl
group or a halogeno-lower alkyl group, and B' represents a group of
the general formula (10).
19. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 13, wherein B' represents a group of the
general formula (10) wherein Z represents a nitrogen atom and J
represents a hydrogen atom, C' and E' represent a lower alkyl
group, and Y' represents a group of the general formula (12)
wherein R.sup.26 represents a substituted or unsubstituted aryl
group and h=2.
20. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 18, wherein B' represents a group of the
general formula (10) wherein Z represents a nitrogen atom and J
represents a hydrogen atom, C' and E' represent a lower alkyl
group, Y' represents a group of the general formula (12) wherein
R.sup.26 represents a substituted or unsubstituted aryl group and
h=2, and X' represents an oxygen atom.
21. The pyridine derivatives, and pharmaceutically acceptable salts
thereof according to claim 12, wherein A' represents 3-chlorophenyl
group, B' represents a carboxyl group, C' and E' represent a methyl
group, X' represents an oxygen atom, Y' and F' together form a
group of the general formula (12"-1), i represents an integer of 3
and R.sup.32, R.sup.33, R.sup.34 and R.sup.35 represent a hydrogen
atom.
22. An N-type calcium channel antagonist comprising a pyrimidine
derivative and a pyridine derivative, or a pharmaceutically
acceptable salt thereof according to any of claims 1 to 7, 10 to
17, 20 and 21 as an active ingredient.
23. An N-type calcium channel antagonist comprising a pyrimidine
derivative and a pyridine derivative, or a pharmaceutically
acceptable salt thereof according to any of claims 8, 9, 18 and 19
as an active ingredient.
24. A pharmaceutical composition comprising a pyrimidine derivative
and a pyridine derivative, or a pharmaceutically acceptable salt
thereof according to any of claims 1 to 7, 10 to 17, 20 and 21 as
an active ingredient.
25. A pharmaceutical composition comprising a pyrimidine derivative
and a pyridine derivative, or a pharmaceutically acceptable salt
thereof according to any of claims 8, 9, 18 and 19 as an active
ingredient.
26. A therapeutic agent comprising a pyrimidine derivative and a
pyridine derivative or a pharmaceutically acceptable salt thereof
according to any of claims 1 to 7, 10 to 17, 20 and 21 as the
active ingredient, for any of acute stage of ischemic
cerebrovascular disorders caused by cerebral infarction or
intracerebral bleeding, Alzheimer's disease, AIDS related dementia,
Parkinson's disease, progressive neurodegenerative diseases,
neuropathy caused by head injury, pain caused by thrormiboangiitis
obliterans, neuropathic pain, migraine, visceral pain, cancer pain,
bronchial asthma, unstable angina, irritable colitis and withdrawal
symptoms after addiction to drugs.
27. A therapeutic agent comprising a pyrimidine derivative and a
pyridine derivative or a pharmaceutically acceptable salt thereof
according to any of claims 8, 9, 18 and 19 as the active
ingredient, for any of acute stage of ischemic cerebrovascular
disorders caused by cerebral infarction or intracerebral bleeding,
Alzheimer's disease, AIDS related dementia, Parkinson's disease,
progressive neurodegenerative diseases, neuropathy caused by head
injury, pain caused by thromboangiitis obliterans, neuropathic
pain, migraine, visceral pain, cancer pain, bronchial asthma,
unstable angina, irritable colitis and withdrawal symptoms after
addiction to drugs.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to new pyrimidine derivatives
and the use of the pyrimidine derivatives as medicines. The present
invention also relates to new pyridine derivatives and the use of
the pyridine derivatives as medicines. The association of the
activation of N-type calcium channels is suggested in various
diseases, for example, acute stage of ischemic cerebrovascular
disorders such as cerebral infarction or intracerebral bleeding
(including subarachnoidal hemorrhage); progressive
neurodegenerative diseases such as Alzheimer's disease, AIDS
related dementia, Parkinson's disease, dementia due to
cerebrovascular disorder and ALS; neuropathy caused by head injury;
various pains such as pains caused by spinal injury, diabetes or
thromboangiitis obliterans, neuropathic pain, migraine, visceral
pain and cancer pain; bronchial asthma; various diseases associated
with psychogenic stress such as unstable angina and irritable
colitis; withdrawal symptoms after addiction to drugs such as
emotional disorder and ethanol addiction withdrawal symptoms. The
compounds of the present invention can inhibit the N-type calcium
channels. The present invention relates to the compounds usable as
therapeutic agents for these diseases.
[0002] Calcium channels are now classified into subtypes of L, N,
P, Q, R and T. Each subtype of calcium channels is
organ-specifically distributed. It is known that particularly
N-type calcium channels are widely distributed in central nerves,
peripheral nerves and adrenomedullary cells and participates in
neuronal cell death, regulation of blood catecholamine level and
control of senses such as perception.
[0003] It has been confirmed that omega-conotoxin GVIA and
omega-conotoxin MVIIA, which are peptides selectively inhibiting
N-type calcium channels, inhibit the release of excitatory
neurotransmitters in the sliced brain preparation. It is also
confirmed in animal experiments that they inhibit the progress of
neuronal necrosis associated with cerebrovascular disorders. It is
generally considered that compounds having a N-type calcium channel
blocking activity are clinically effective in the treatment of
acute stage of ischemic cerebrovascular disorders such as cerebral
infarction or intracerebral bleeding (including subarachnoidal
hemorrhage); progressive neurodegenerative diseases such as
Alzheimer's disease, AIDS related dementia, Parkinson's disease,
dementia due to cerebrovascular disorder and ALS; and neuropathy
caused by head injury. Further, it is confirmed in animal tests
that omega-conotoxin MVIIA relieves a pain induced by formalin, hot
plate and peripheral neuropathy (J. Pharmacol. Exp. Ther. 269 (3)
1117-1123, 1994.; J. Pharmacol. Exp. Ther. 274 (2) 666-672, 1995).
Accordingly, omega-conotoxin MVIIA is considered to be clinically
effective against various pains such as pain caused by spinal
injury, diabetes or thromboangiitis obliterans, neuropathic pain
(for example, post herpetic neuralgia, diabetic nephropathy,
complex regional pain syndrome, avulsion injury of the brachial
plexus, trigeminal neuralgia, pain from spinal injury, central pain
and postoperative pain), migraine, visceral pain and cancer pain.
In addition, because omega-conotoxin GVIA inhibits the release of
catecholamine from cultured sympathetic ganglion cells, exaltation
of catecholamine secretion from canine adrenal medulla and the
contraction of the isolated blood vessel by electric stimulation of
the perivascular nerve, it is considered that compounds having
N-type calcium channel-blocking effects are clinically effective
against bronchial asthma, various diseases related to psychogenic
stress such as unstable angina and irritable colitis
(Neuropharmacol., 32, 1141, 1993).
[0004] Some peptidergic and non-peptidergic compounds which
selectively affect N-type calcium channels have been ever disclosed
(see, for example, WO 9313128, WO 9849144, WO9901438 and
WO9932446). However, none of them was actually used as a medicine.
Some of the compounds which affect N-type calcium channels are also
effective against various types of calcium channels of other than
N-type (British Journal of Pharmacology, 122 (1) 37-42, 1997). For
example, compounds having an antagonistic effect on L-type calcium
channels (the channels that are locally distributed in various
organs such as vascular smooth muscles) which are very closely
related to hypotensive effect, could not be used for diseases for
which N-type calcium channel antagonists will be used (such as
cerebral stroke, neuralgia, terminal cancer pain and pain of spinal
injury). Under these circumstances, the development of a highly
active antagonist selective toward N-type calcium channels (the
channels that exist in the nervous system) has been eagerly
demanded. Recently, improvement in QOL (Quality of life) of the
patients is demanded, and medicines to be taken orally are
considered to be necessary. Especially, when the medicines are used
as analgesic agents to terminal cancer patients and spinal injury
victims, less frequent doses and lower dosage will further improve
QOL.
[0005] However, N-type calcium channel antagonists well-known in
the art were yet unsatisfactory for solving this problem because
some of them are peptides which cannot be absorbed in the digestive
organs or some of them are chemically unstable and, therefore,
decomposed in the digestive organs. Though N-type calcium channel
antagonists can be absorbed in the digestive organs, the compounds
that have less first-pass effect and high durability of drug
efficacy cannot be found yet. In addition, some of the well-known
compounds are those which have asymmetric carbons. The compounds
having an asymmetric carbon have optical isomers, and the activity,
toxicity and pharmacokinetics between the isomers are generally
believed to be different from each other. Therefore, the chiral
compounds having extremely high optical purity or the achiral
compounds without asymmetric carbon have been desired in order to
develop the pharmaceutical compounds.
[0006] Meanwhile, various pyrimidine derivatives and pyridine
derivatives have been reported (WO 9204333, WO 9919302, WO 0073279,
Laid-open No. 2000-247957, Laid-open No. Hei 7-101940, Laid-open
No. Hei 9-241161, Publication No. Sho 48-21949, J. Med. Chem. 31
(6) 1231-1240, 1988. and Chem. Pharm. Bull. 40 (9) 2423-2431,
1992). However, any prior arts did not describe that the reported
compounds and similar pyrimidine derivatives and pyridine
derivatives inhibited selectively N-type calcium channels. For
instance, Laid-open No. Hei 9-241161 describes that
4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine
derivatives inhibit neuronal necrosis and, therefore, are effective
in the treatment of post cerebrovascular disorders. However, the
said compound is a voltage-dependent Na.sup.+/Ca.sup.2+ channel
inhibitor (Eur. J. Pharmacol. 336, 283-290, 1997.) and not expected
as selective antagonist to N-type calcium channels.
DISCLOSURE OF THE INVENTION
[0007] The object of the present invention is to provide new
compounds having a selective antagonistic effect on N-type calcium
channels.
[0008] Another object of the present invention is to provide
antagonists against N-type calcium channels.
[0009] A further object of the present invention is to provide a
therapeutic agent for any of acute stage of ischemic
cerebrovascular disorders such as cerebral infarction or
intracerebral bleeding, Alzheimer's disease, AIDS related dementia,
Parkinson's disease, progressive neurodegenerative diseases,
neuropathy caused by head injury, pain caused by thromboangiitis
obliterans, neuropathic pain, migraine, visceral pain, cancer pain,
bronchial asthma, unstable angina, irritable colitis and withdrawal
symptoms after addiction to drugs.
[0010] A further object of the present invention is to provide a
pharmaceutical composition.
[0011] After synthesizing various compounds, having a pyrimidine
nucleus or a pyridine nucleus, which are metabolites of well-known
compounds having a dihydropyrimidine nucleus or a dihydropyridine
nucleus, and examining the N-type calcium channel inhibiting effect
(determined by fluorescent dye method) and L-type calcium channel
inhibiting effect (determined by the relaxation after KCl-induced
contraction of samples of isolated rat thoracic aorta) of them for
the purpose of solving the above-described problems, the inventors
have found that specified pyrimidine derivatives and pyridine
derivatives have an excellent effect of selectively antagonizing
N-type calcium channels. After examining analgesic effect, one of
effects against above diseases, for confirming usefulness of the
compounds of the present invention, the inventors have found that
the said compounds are orally active and their efficacies are
durable. The present invention has been completed on the basis of
this finding. Further, the compounds of the present invention are
more useful pharmaceutical compounds because they are the achiral
compounds without an asymmetric carbon.
[0012] Namely, the present invention provides pyrimidine
derivatives of the following general formula (1) and
pharmaceutically acceptable salts thereof 2
[0013] wherein A represents a group of the following general
formula (2), or 1-naphthyl, 2-naphthyl, indole-2-yl, indole-3-yl,
thiophene-3-yl, thiophene-2-yl, furan-3-yl, furan-2-yl,
pyridine-4-yl, pyridine-3-yl or pyridine-2-yl group: 3
[0014] wherein R.sup.1, R .sup.2, R.sup.3, R.sup.4 and R.sup.5 may
be the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkylamino group, a lower alkylthio group, a lower alkanoyl
group, a lower alkoxycarbonyl group, a hydroxy-lower alkyl group, a
hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a
halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a
halogeno-lower alkenyl group, an aryl-lower alkoxyl group or an
aroyl group,
[0015] C represents a hydrogen atom, a lower alkyl group, a lower
alkylamino group, a lower alkylthio group, a lower alkyl sulfinyl
group, a lower alkyl sulfonyl group, a lower alkoxyl group, a
hydroxy-lower alkyl group, a hydroxy-lower alkylamino group, a
hydroxy-lower alkylthio group, a hydroxy-lower alkoxyl group, an
amino-lower alkyl group, an amino-lower alkylamino group, an
amino-lower alkylthio group, an amino-lower alkoxyl group, an
aryl-lower alkyl group, an aryl-lower alkylamino group, an
aryl-lower alkylthio group, an aryl-lower alkoxyl group, a
heteroaryl-lower alkyl group, a heteroaryl-lower alkylamino group,
a heteroaryl-lower alkylthio group, a heteroaryl-lower alkoxyl
group, a halogeno-lower alkyl group, a halogeno-lower alkylamino
group, a halogeno-lower alkylthio group, a halogeno-lower alkoxyl
group, a substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, a substituted or unsubstituted
cyclic alkyl group, a lower alkyl group substituted with a
substituted or unsubstituted cyclic alkyl group, a substituted or
unsubstituted aryloxy group or a substituted or unsubstituted
heteroaryloxy group,
[0016] E represents a hydrogen atom, a lower alkyl group,
dimethoxymethyl group, cyano group, an aryl-lower alkyl group, a
heteroaryl-lower alkyl group, a hydroxy-lower alkyl group, an
amino-lower alkyl group, a halogeno-lower alkyl group, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group or a group of the following general
formula (3) or (4): 4
[0017] wherein X.sub.2 represents O, S or N--R.sub.8, n represents
an integer of 1 to 6, K in general formula (3) represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group or azido group, G in the
general formula (4) represents N or C--H, wherein R.sup.6 to
R.sup.8 may be the same or different from each other, and each
represents a hydrogen atom, a linear, branched or cyclic, saturated
or unsaturated hydrocarbon group having 1 to 6 carbon atoms, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, a hydroxy-lower alkyl group, a
hydroxy-lower alkenyl group, an amino-lower alkyl group, an
amino-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkenyl group, an aryl-lower alkyl group, an
aryl-lower alkenyl group, a heteroaryl-lower alkyl group, a
heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a
cyano-lower alkenyl group, and the chains may contain a hetero
atom, or R.sup.6 and R.sup.7 may together form a ring which may
contain a hetero atom,
[0018] F represents a group of the following general formula (5),
thiophene-3-yl, thiophene-2-yl, furan-3-yl, furan-2-yl,
pyridine-4-yl, pyridine-3-yl, pyridine-2-yl group, cyclopentyl
group, cyclohexyl group, morpholine-1-yl, imidazole-1-yl,
pyrrolidine-1-yl, pyrrolidinone-1-yl, piperidine-1-yl,
piperidinone-1-yl or piperazine-1-yl group: 5
[0019] wherein R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13
may be the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkylamino group, a lower alkylthio group, a lower alkanoyl
group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group,
a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an
aryl-lower alkyl group, an aryl-lower alkoxyl group, a lower
alkoxycarbonyl group, an aroyl group, a substituted or
unsubstituted aryl group, a substituted or unsubstituted heteroaryl
group or a saturated cyclic hydrocarbon group having 3 to 8 carbon
atoms, which may contain a hetero atom in the chain thereof and/or
the ring thereof,
[0020] X.sub.1 represents >N--R.sup.14 wherein R.sup.14
represents a hydrogen atom, a lower alkyl group which may contain a
hetero atom in the chain thereof, a hydroxy-lower alkyl group, an
amino-lower alkyl group, a carboxy-lower alkyl group or a lower
alkyloxycarbonyl-lower alkyl group,
[0021] Y represents a saturated or unsaturated linear hydrocarbon
group having 1 to 6 carbon atoms, which may contain a hetero atom
in the group thereof, or a group of the following general formula
(6): 6
[0022] wherein R.sub.15 represents a hydrogen atom, a substituted
or unsubstituted, saturated or unsaturated linear, branched or
cyclic hydrocarbon group having 1 to 6 carbon atoms, a substituted
or unsubstituted aryl group, a substituted or unsubstituted
heteroaryl group, a hydroxy-lower alkyl group, a hydroxy-lower
alkenyl group, an amino-lower alkyl group, an amino-lower alkenyl
group, a halogeno-lower alkyl group, a halogeno-lower alkenyl
group, an aryl-lower alkyl group, an aryl-lower alkenyl group, a
heteroaryl-lower alkyl group, a heteroaryl-lower alkenyl group, a
cyano-lower alkyl group or a cyano-lower alkenyl group, and the
chains of R.sup.15 may contain a hetero atom, and m represents an
integer of 0 to 5.
[0023] The present invention also provides pyridine derivatives of
the following general formula (1') and pharmaceutically acceptable
salts thereof. 7
[0024] wherein A represents a group of the following general
formula (2), or 1-naphthyl, 2-naphthyl, indole-2-yl, indole-3-yl,
thiophene-3-yl, thiophene-2-yl, furan-3-yl, furan-2-yl,
pyridine-4-yl, pyridine-3-yl or pyridine-2-yl group: 8
[0025] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 may
be the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkylamino group, a lower alkylthio group, a lower alkanoyl
group, a lower alkoxycarbonyl group, a hydroxy-lower alkyl group, a
hydroxy-lower alkoxyl group, a hydroxy-lower alkenyl group, a
halogeno-lower alkyl group, a halogeno-lower alkoxyl group, a
halogeno-lower alkenyl group, an aryl-lower alkoxyl group or an
aroyl group,
[0026] C represents a hydrogen atom, a lower alkyl group, a lower
alkylamino group, a lower alkylthio group, a lower alkyl sulfinyl
group, a lower alkyl sulfonyl group, a lower alkoxyl group, a
hydroxy-lower alkyl group, a hydroxy-lower alkylamino group, a
hydroxy-lower alkylthio group, a hydroxy-lower alkoxyl group, an
amino-lower alkyl group, an amino-lower alkylamino group, an
amino-lower alkylthio group, an amino-lower alkoxyl group, an
aryl-lower alkyl group, an aryl-lower alkylamino group, an
aryl-lower alkylthio group, an aryl-lower alkoxyl group, a
heteroaryl-lower alkyl group, a heteroaryl-lower alkylamino group,
a heteroaryl-lower alkylthio group, a heteroaryl-lower alkoxyl
group, a halogeno-lower alkyl group, a halogeno-lower alkylamino
group, a halogeno-lower alkylthio group, a halogeno-lower alkoxyl
group, a substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, a substituted or unsubstituted
cyclic alkyl group, a lower alkyl group substituted with a
substituted or unsubstituted cyclic alkyl group, a substituted or
unsubstituted aryloxy group or a substituted or unsubstituted
heteroaryloxy group,
[0027] E represents a hydrogen atom, a lower alkyl group,
dimethoxymethyl group, cyano group, an aryl-lower alkyl group, a
heteroaryl-lower alkyl group, a hydroxy-lower alkyl group, an
amino-lower alkyl group, a halogeno-lower alkyl group, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group or a group of the following general
formula (3) or (4): 9
[0028] wherein X.sub.2 represents O, S or N--R.sub.8, n represents
an integer of 1 to 6, K in general formula (3) represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group or azido group, G in the
general formula (4) represents N or C--H, wherein R.sup.6 to
R.sup.8 may be the same or different from each other, and each
represents a hydrogen atom, a linear, branched or cyclic, saturated
or unsaturated hydrocarbon group having 1 to 6 carbon atoms, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, a hydroxy-lower alkyl group, a
hydroxy-lower alkenyl group, an amino-lower alkyl group, an
amino-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkenyl group, an aryl-lower alkyl group, an
aryl-lower alkenyl group, a heteroaryl-lower alkyl group, a
heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a
cyano-lower alkenyl group, and the chains may contain a hetero
atom, or R.sup.6 and R.sup.7 may together form a ring which may
contain a hetero atom,
[0029] F represents a group of the following general formula (5),
or thiophene-3-yl, thiophene-2-yl, furan-3-yl, furan-2-yl,
pyridine-4-yl, pyridine-3-yl or pyridine-2-yl group, cyclopentyl
group, cyclohexyl group, morpholine-1-yl, imidazole-1-yl,
pyrrolidine-1-yl, pyrrolidinone-1-yl, piperidine-1-yl,
piperidinone-1-yl or piperazine-1-yl group: 10
[0030] wherein R.sup.9, R.sup.10, R.sup.11, R.sup.12 and R.sup.13
may be the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group, a lower alkenyl group, a lower alkynyl group, a
lower alkylamino group, a lower alkylthio group, a lower alkanoyl
group, a hydroxy-lower alkyl group, a hydroxy-lower alkoxyl group,
a hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkoxyl group, a halogeno-lower alkenyl group, an
aryl-lower alkyl group, an aryl-lower alkoxyl group, a lower
alkoxycarbonyl group, an aroyl group, a substituted or
unsubstituted aryl group, a substituted or unsubstituted heteroaryl
group or a saturated cyclic hydrocarbon group having 3 to 8 carbon
atoms, which may contain a hetero atom in the chain thereof and/or
the ring thereof,
[0031] X.sub.3 represents a group of the following general formula
(7) or (8): 11
[0032] Y represents a saturated or unsaturated linear hydrocarbon
group having 2 to 6 carbon atoms, which may contain a hetero atom
in the group thereof, or a group of the following general formula
(6): 12
[0033] wherein R.sub.15 represents a hydrogen atom, a substituted
or unsubstituted, saturated or unsaturated linear, branched or
cyclic hydrocarbon group having 1 to 6 carbon atoms, a substituted
or unsubstituted aryl group, a substituted or unsubstituted
heteroaryl group, a hydroxy-lower alkyl group, a hydroxy-lower
alkenyl group, an amino-lower alkyl group, an amino-lower alkenyl
group, a halogeno-lower alkyl group, a halogeno-lower alkenyl
group, an aryl-lower alkyl group, an aryl-lower alkenyl group, a
heteroaryl-lower alkyl group, a heteroaryl-lower alkenyl group, a
cyano-lower alkyl group or a cyano-lower alkenyl group, and the
chains of R.sup.15 may contain a hetero atom, and m represents an
integer of 1 to 5.
[0034] The present invention also provides pyrimidine derivatives
of the following general formula (1") and pharmaceutically
acceptable salts thereof 13
[0035] wherein A' represents a group of the following general
formula (9): 14
[0036] wherein R.sup.16, R.sup.17, R.sup.18, R.sup.19 and R.sup.20
may be the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group or a lower alkylamino group,
[0037] C' and E' may be the same or different from each other and
each represents a hydrogen atom, a lower alkyl group which may
contain a hetero atom in the chain thereof, dimethoxymethyl group,
cyano group, an aryl-lower alkyl group, a heteroaryl-lower alkyl
group, a hydroxy-lower alkyl group, an amino-lower alkyl group, a
halogeno-lower alkyl group, a substituted or unsubstituted aryl
group, a substituted or unsubstituted heteroaryl group or a group
of t,he following general formula (3) or (4): 15
[0038] wherein X.sub.2 represents O, S or N--R.sub.8, n represents
an integer of 1 to 6, K in general formula (3) represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, azido group, a substituted
or unsubstituted aryl group or a substituted or unsubstituted
heteroaryl group, G in the general formula (4) represents N or
C--H, wherein R.sup.6 to R.sup.8 may be the same or different from
each other, and each represents a hydrogen atom, a linear, branched
or cyclic, saturated or unsaturated hydrocarbon group having 1 to 6
carbon atoms, a substituted or unsubstituted aryl group, a
substituted or unsubstituted heteroaryl group, a hydroxy-lower
alkyl group, a hydroxy-lower alkenyl group, an amino-lower alkyl
group, an amino-lower alkenyl group, a halogeno-lower alkyl group,
a halogeno-lower alkenyl group, an aryl-lower alkyl group, an
aryl-lower alkenyl group, a heteroaryl-lower alkyl group, a
heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a
cyano-lower alkenyl group, and the chains may contain a hetero
atom, or R.sup.6 and R.sup.7may together form a ring which may
contain a hetero atom,
[0039] B' represents a hydrogen atom only when Y' represents the
general formula (12) and R.sup.26 is a substituted or unsubstituted
aryl group, a carboxyl group only when Y' represents the general
formula (12) or Y' and F' together form the following general
formula (12'-1), (12'-2), (12"-l) or (12"-2), or a group of the
following general formula (10): 16
[0040] wherein Z represents a nitrogen atom, an oxygen atom or a
carbon atom, p represents an integer of 1 to 3, J represents an
unsubstituted group only when Z is an oxygen atom, a hydrogen atom,
a lower alkyl group which may contain a hetero atom in the group
thereof, a hydroxy-lower alkyl group, an amino-lower alkyl group, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, a substituted or unsubstituted
aryl-lower alkyl group or a substituted or unsubstituted
heteroaryl-lower alkyl group,
[0041] F' represents the following general formula (11): 17
[0042] wherein R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.25
may be the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group, a lower alkylamino group, a substituted or
unsubstituted aryl group or a substituted or unsubstituted
heteroaryl group,
[0043] X' represents an oxygen atom or >NH,
[0044] Y represents a saturated or unsaturated linear hydrocarbon
group having 1 to 6 carbon atoms, which may contain a hetero atom
in the group thereof, or a group of the following general formula
(12): 18
[0045] wherein R.sup.26 represents a substituted or unsubstituted
aryl group or a substituted or unsubstituted heteroaryl group and h
represents an integer of 0 to 5, Y' and F' together form a group of
the following general formula (12'-1), (12'-2), (12"-1) or (12"-2):
19
[0046] wherein h represents an integer of 0 to 5, i represents an
integer of 2 to 5, R.sup.32, R.sup.33, R.sup.34 and R.sup.35 may be
the same or different from each other and each represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group, a lower alkyl group, a lower
alkoxyl group, a lower alkylamino group, a substituted or
unsubstituted aryl group or a substituted or unsubstituted
heteroaryl group.
[0047] The present invention provides an N-type calcium channel
antagonist containing the above-described pyrimidine derivative or
pyridine derivative, or a pharmaceutically acceptable salt thereof
as the active ingredient.
[0048] The present invention also provides a pharmaceutical
composition containing the above-described pyrimidine derivative or
pyridine derivative, or a pharmaceutically acceptable salt thereof
as the active ingredient.
[0049] The present invention also provides a therapeutic agent
containing the above-described pyrimidine derivative or pyridine
derivative, or a pharmaceutically acceptable salt thereof as the
active ingredient, for any of acute stage of ischemic
cerebrovascular disorders caused by cerebral infarction or
intracerebral bleeding, Alzheimer's disease, AIDS related dementia,
Parkinson's disease, progressive neurodegenerative diseases,
neuropathy caused by head injury, pain caused by thromboangiitis
obliterans, neuropathic pain, migraine, visceral pain, cancer pain,
bronchial asthma, unstable angina, irritable colitis and withdrawal
symptoms after addiction to drugs.
BEST MODE FOR CARRYING OUT THE INVENTION
[0050] The term "lower" herein indicates that the group has 1 to 6
carbon atoms. Alkyl groups themselves and also alkyl groups in
alkenyl groups, alkynyl groups, alkoxyl groups, alkylamino groups,
alkylthio groups, alkanoyl groups, alkyl sulfinyl groups, alkyl
sulfonyl groups and the like may be either linear or branched.
Examples of these alkyl groups are methyl group, ethyl group,
propyl group, isopropyl group, butyl group, secondary and tertiary
butyl groups, pentyl group and hexyl group. Among them, those
having 1 to 3 carbon atoms are preferred. The aryl-lower alkyl
groups include, for example, benzyl group. The heteroaryl-lower
alkyl groups include, for example, pyridylmethyl group. The
aryl-lower alkoxyl groups include, for example, benzyloxy group.
The hetero atoms include nitrogen, oxygen, sulfur, etc. The halogen
atoms include fluorine, chlorine, bromine and iodine atoms. In the
present specification, the aryl groups are both substituted and
unsubstituted aryl groups. They are preferably phenyl group and
substituted phenyl group, and the substituents are particularly
preferably halogens, alkyl groups and alkoxyl groups. The
heteroaryl groups are substituted or unsubstituted heteroaryl
groups such as, preferably, pyridyl group, furyl group and thienyl
group, and also substituted pyridyl, furyl and thienyl groups.
Halogens, alkyl groups and alkoxyl groups are particularly
preferred as the substituents. The cyclic alkyl groups include, for
example, cyclopentyl groups and cyclohexyl groups. The cyclic alkyl
groups which may contain a hetero atom in the ring thereof include,
for example, piperidinyl groups, morpholinyl groups and piperazinyl
groups. Examples of the cyclic alkyl groups substituted with the
cyclic alkyl group are cyclopentylethyl groups and cyclohexylmethyl
groups. The cyclic alkyl groups which may contain a hetero atom in
the ring thereof include, for example, piperidinylmethyl groups,
morpholinylmethyl groups and piperazinylmethyl groups. The aroyl
groups include, for example, benzoyl group and pyridylcarbonyl
group. The hydrocarbon groups indicate alkyl groups, alkenyl groups
and alkynyl groups. The saturated hydrocarbon groups indicate alkyl
groups such as methyl group, ethyl group, propyl group, isopropyl
group, butyl group, pentyl group, hexyl group and sec. and tert.
butyl groups. The unsaturated hydrocarbon groups indicate alkenyl
groups and alkynyl groups. The alkenyl groups include propenyl
group, butenyl group, pentenyl group, etc. The alkynyl groups
include ethynyl group, propinyl group, butynyl group, etc. Examples
of the cyclic hydrocarbon groups include cyclopentyl group and
cyclohexyl group. Examples of the cyclic hydrocarbon groups which
may contain a hetero atom in the chain thereof include piperidyl
group, pyrrolidinyl group and piperazinyl group. The hydrocarbon
groups and alkyl groups which may contain a hetero atom in the
chain or group thereof include, for example, alkoxyl groups,
alkylamino groups, alkylthio groups, alkoxymethyl groups and
alkylaminoethyl groups.
[0051] 1-naphthyl group, 2-naphthyl group, indole-2-yl group and
indole-3-yl group represented by A in the above general formula (1)
are either unsubstituted or substituted. The substituents are those
listed above for R.sup.1 to R.sup.5.
[0052] Thiophene-3-yl group, thiophene-2-yl group, furan-3-yl
group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group
and pyridine-2-yl group represented by A are also either
unsubstituted or substituted. When two or more substituents are
contained therein, they may form a ring together. The substituents
are those described above with reference to 1-naphthyl group or the
like. The rings formed by those groups include benzothiophene,
benzofuran, quinoline, isoquinoline, etc.
[0053] A is preferably a group represented by the general formula
(2).
[0054] R.sup.1 to R.sup.5 that are substituents of a group of the
general formula (2) are preferably a halogen atom, a lower-alkyl
group, etc.
[0055] The groups represented by C in the general formula (1),
namely, lower-alkyl groups, aryl lower-alkyl groups, heteroaryl
lower-alkyl groups may contain a hetero atom in the chain thereof,
or may form a ring or branch.
[0056] Cyclic alkyl groups and lower-alkyl groups substituted with
a cyclic alkyl group, which are also the groups represented by C,
may contain a hetero atom in the ring thereof. The cyclic alkyl
groups include, for example, cyclopentyl groups and cyclohexyl
groups. The cyclic alkyl groups which may contain a hetero atom in
the ring thereof include piperidinyl groups, morpholinyl groups,
piperazinyl groups and so on. Examples of the lower-alkyl groups
substituted with the cyclic alkyl group are cyclopentylethyl groups
and cyclohexylmethyl groups. The cyclic alkyl groups which may
contain a hetero atom in the ring thereof include piperidinylmethyl
groups, morpholinylmethyl groups, piperazinylmethyl groups and
(piperidine-1-yl)ethoxy groups.
[0057] Aryl groups and heteroaryl groups represented by C are
either substituted or unsubstituted. Their substituents are those
listed above for R.sup.1 to R.sup.5 in the general formula (1).
[0058] Substituted or unsubstituted aryloxy groups and substituted
or unsubstituted heteroaryloxy groups, which are the groups
represented by C, include phenoxy groups, naphthyloxy groups and
pyridyloxy groups. The substituents thereof are those listed above
for R.sup.1 to R.sup.5in the general formula (1).
[0059] Aryl lower-alkyl groups, aryl lower-alkylamino groups, aryl
lower-alkylthio groups, aryl lower-alkoxy groups, heteroaryl
lower-alkyl groups, heteroaryl lower-alkylamino groups, heteroaryl
lower-alkylthio groups and heteroaryl lower-alkoxy groups, which
are also represented by C, include, for example, 3-phenylpropyl
group, 2-phenylethylamino group, 2-phenylethoxy group,
3-pyridine-2-yl) propyl group, 2-(pyridine-3-yl) ethylamino group,
2-(pyridine-2-yl) ethoxy group and phenoxymethyl group.
[0060] Amino groups in amino lower-alkyl groups, amino
lower-alkylamino groups, amino lower-alkylthio groups and amino
lower-alkoxy groups, which are also represented by C, may combine
with cyclic aliphatic amine, which may contain a hetero atom in the
ring thereof. The ring herein indicates 3- to 8-membered ring and
its examples are piperidine-1-yl, piperidine-4-yl,
pyrrolidine-1-yl, pyrrolidine-3-yl, piperidinone-1-yl,
pyrrolidinone-1-yl, piperazine-1-yl and morpholine-4-yl group.
Their substituents are, for example, 2-(piperidine-1-yl)ethyl
group, 2-(piperidine-1-yl)ethylamino group,
2-(piperidine-1-yl)ethylthio group, 2-(piperidine-1-yl)ethoxy
group, aminoethyl group, aminoethylamino group, aminoethylthio
group and aminoethoxy group.
[0061] A lower-alkyl sulfinyl group, which are also represented by
C, includes a methylsulfinyl group. A lower-alkyl sulfonyl group
includes, for example, a methylsulfonyl group.
[0062] The groups represented by C in the above general formula (1)
are preferably lower-alkyl groups, lower-alkylamino groups, lower
alkylthio groups or lower-alkoxy groups, and most preferably ethyl
groups, propyl groups or methylthio groups.
[0063] K represented by the general formula (3) in the groups
represented by E in the above general formula (1) represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group or azido group. K is
preferably a hydrogen atom, hydroxyl group, carboxyl group or amino
group.
[0064] The groups represented by R.sup.6 or R.sup.7 in the groups
represented by the general formula (4) in the groups represented by
E in the above general formula (1) each represent a hydrogen atom,
a linear, branched or cyclic, saturated or unsaturated hydrocarbon
group having 1 to 6 carbon atoms, a substituted or unsubstituted
aryl group, a substituted or unsubstituted heteroaryl group, a
hydroxy-lower alkyl group, a hydroxy-lower alkenyl group, a
halogeno-lower alkyl group, a halogeno-lower alkenyl group, an
aryl-lower alkyl group, an aryl-lower alkenyl group, a
heteroaryl-lower alkyl group, a heteroaryl-lower alkenyl group, a
cyano-lower alkyl group or a cyano-lower alkenyl group, and the
chains may contain a hetero atom thereof, or R.sup.6 and R.sup.7
may together form a ring which may contain a hetero atom thereof
The linear, branched or cyclic, saturated or unsaturated
hydrocarbon group having 1 to 6 carbon atoms herein include, for
example, methyl group, ethyl group, propyl group, isopropyl group,
cyclopentyl group, cyclohexyl group, allyl group and vinyl group.
Methyl group and ethyl group are preferred. The substituents in the
substituted or unsubstituted aryl groups or substituted or
unsubstituted heteroaryl groups represented by R.sup.6 or R.sup.7
are those described above with reference to R.sup.1 to R.sup.5 in
the general formula (1).
[0065] R.sup.6 and R.sup.7 may be bonded together to form a ring
with G. The ring may contain a hetero atom. The rings herein are 3-
to 8-membered rings such as cyclopentyl group, cyclohexyl group,
piperidine-1-yl group, piperidine-4-yl group, pyrrolidine-1-yl
group, pyrrolidine-3-yl group, piperidinone-1-yl group,
pyrrolidinone-1-yl group, piperazine-1-yl group and morpholine-4-yl
group.
[0066] Group E in the general formula (1) is preferably a lower
alkyl group, methoxymethyl group, 2-aminoethoxymethyl group,
2-hydroxyethoxymethyl group, 2-carboxyethoxymethyl group, or a
group of the general formula (3). Group E is particularly
preferably methyl group, a group of the general formula (4) wherein
X.sub.2 represents an oxygen atom, n represents an integer of 2 or
3 and R.sup.6 and R.sup.7 are bonded together to form a 5- to
7-membered ring with G (G is preferably N or C--H), such as
2-cyclohexylethoxymethyl group or 2-piperidino-ethoxymethyl
group.
[0067] Group F is preferably a group of the general formula
(5).
[0068] A lower-alkyloxycarbonyl lower-alkyl group represented by
>N--R.sup.14 in the group represented by X.sub.1 includes an
ethoxycarboxymethyl group.
[0069] Group X.sub.1 is particularly preferably a group represented
by >N--R.sup.14 wherein R.sup.14 represents a hydrogen atom.
[0070] Group Y is preferably a group of the general formula (6)
wherein m represents an integer of 1 or 4 and R.sup.15 represents
an aryl groups, or a saturated or unsaturated hydrocarbon group
having 3 to 4 carbon atoms. Particularly, 3-phenylpropyl group or
3-phenyl-2-propen-1-yl group is preferred.
[0071] In the present invention represented by the general formula
(1), F is preferably a group of the general formula (5),
thiophene-3-yl group, thiophene-2-yl group, furan-3-yl group or
furan-2-yl group, and Y is preferably a saturated or unsaturated
linear hydrocarbon group having 2 to 6 carbon atoms, which may
contain a hetero atom in the group thereof, or a group of the
general formula (6) wherein m is an integer of 1 to 5.
[0072] It is preferred in the present invention that A represents a
group of the general formula (2), F represents a group of the
general formula (5) and X.sub.1 represents >N--R.sup.14 wherein
R.sup.14 represents a hydrogen atom.
[0073] It is preferred in the present invention that A represents a
group of the general formula (2), C represents a lower-alkyl group,
F represents a group of the general formula (5), X.sub.1 represents
>N--R.sup.14 wherein R.sup.14 represents a hydrogen atom, and Y
represents a saturated or unsaturated hydrocarbon group having 3
carbon atoms.
[0074] It is preferred in the present invention that A represents a
group of the general formula (2), C represents a lower-alkylthio
group, a lower-alkyl sulfinyl group or a lower-alkyl sulfonyl
group, F represents a group of the general formula (5), X.sub.1
represents >N--R.sup.14 wherein R.sup.14 represents a hydrogen
atom, and Y represents a saturated or unsaturated hydrocarbon group
having 3 carbon atoms.
[0075] It is preferred in the present invention that A represents a
group of the general formula (2), C represents a lower-alkyl group,
E represents a methyl group, F represents a group of the general
formula (5), X.sub.1 represents >N--R.sup.14 wherein R.sup.14
represents a hydrogen atom, and Y represents a saturated or
unsaturated hydrocarbon group having 3 carbon atoms.
[0076] It is preferred in the present invention that A represents a
group of the general formula (2), C represents a lower-alkylthio
group, E represents a methyl group, F represents a group of the
general formula (5), X.sub.1 represents >N--R.sup.14 wherein
R.sup.14 represents a hydrogen atom and Y represents a saturated or
unsaturated hydrocarbon group having 3 carbon atoms.
[0077] It is preferred in the present invention that C represents a
hydrogen atom, a lower alkyl group which may contain a hetero atom
in the chain thereof, a lower alkylamino group, a lower alkylthio
group, a lower alkoxyl group, a hydroxy-lower alkyl group, a
hydroxy-lower alkylamino group, a hydroxy-lower alkylthio group, a
hydroxy-lower alkoxyl group, an amino-lower alkyl group, an
amino-lower alkylamino group, an amino-lower alkylthio group, an
amino-lower alkoxyl group, an aryl-lower alkyl group which may
contain a hetero atom in the chain thereof, an aryl-lower
alkylamino group, an aryl-lower alkylthio group, an aryl-lower
alkoxyl group, a heteroaryl-lower alkyl group, a heteroaryl-lower
alkylamino group, a heteroaryl-lower alkylthio group, a
heteroaryl-lower alkoxyl group, a halogeno-lower alkyl group, a
halogeno-lower alkylamino group, a halogeno-lower alkylthio group,
a halogeno-lower alkoxyl group, a substituted or unsubstituted aryl
group, or a substituted or unsubstituted heteroaryl group.
[0078] It is preferred in the present invention that C represents a
hydrogen atom, a lower alkyl group which may contain a hetero atom
in the chain thereof, a lower alkylamino group, a lower alkylthio
group, a lower alkoxyl group, a hydroxy-lower alkyl group, a
hydroxy-lower alkylamino group, a hydroxy-lower alkylthio group, a
hydroxy-lower alkoxyl group, an amino-lower alkyl group, an
amino-lower alkylamino group, an amino-lower alkylthio group, an
amino-lower alkoxyl group, an aryl-lower alkyl group which may
contain a hetero atom in the chain thereof, an aryl-lower
alkylamino group, an aryl-lower alkylthio group, an aryl-lower
alkoxyl group, a heteroaryl-lower alkyl group, a heteroaryl-lower
alkylamino group, a heteroaryl-lower alkylthio group, a
heteroaryl-lower alkoxyl group, a halogeno-lower alkyl group, a
halogeno-lower alkylamino group, a halogeno-lower alkylthio group,
a halogeno-lower alkoxyl group, a substituted or unsubstituted aryl
group, or a substituted or unsubstituted heteroaryl group, A
represents a group of the general formula (2), C represents a
lower-alkyl group or a lower-alkylthio group, F represents a group
of the general formula (5), X.sub.1 represents >N--R.sup.14
wherein R.sup.14 represents a hydrogen atom, and Y represents a
saturated or unsaturated hydrocarbon group having 3 to 4 carbon
atoms.
[0079] Next, the explanation on the compounds represented by the
general formula (1') is given below. 1-naphthyl group, 2-naphthyl
group, indole-2-yl group and indole-3-yl group represented by A in
the above general formula (1') are either unsubstituted or
substituted. The substituents are those listed above for R.sup.1 to
R.sup.5.
[0080] Thiophene-3-yl group, thiophene-2-yl group, furan-3-yl
group, furan-2-yl group, pyridine-4-yl group, pyridine-3-yl group
and pyridine-2-yl group represented by A are also either
unsubstituted or substituted. When two or more substituents are
contained therein, they may form a ring together. The substituents
are those described above with reference to 1-naphthyl group or the
like. The rings formed by those groups include benzothiophene,
benzofuran, quinoline, isoquinoline, etc.
[0081] A is preferably a group represented by the general formula
(2).
[0082] The groups represented by C in the general formula (1')
represents a lower alkyl group, a lower alkylamino group, a lower
alkylthio group, a lower alkyl sulfinyl group, a lower alkyl
sulfonyl group, a lower alkoxyl group, a hydroxy-lower alkyl group,
a hydroxy-lower alkylamino group, a hydroxy-lower alkylthio group,
a hydroxy-lower alkoxyl group, an amino-lower alkyl group, an
amino-lower alkylamino group, an amino-lower alkylthio group, an
amino-lower alkoxyl group, an aryl-lower alkyl group, an aryl-lower
alkylamino group, an aryl-lower alkylthio group, an aryl-lower
alkoxyl group, a heteroaryl-lower alkyl group, a heteroaryl-lower
alkylamino group, a heteroaryl-lower alkylthio group, a
heteroaryl-lower alkoxyl group, a halogeno-lower alkyl group, a
halogeno-lower alkylamino group, a halogeno-lower alkylthio group,
a halogeno-lower alkoxyl group, piperidinyl group, morpholinyl
group, piperazinyl groups, piperidinyl-lower alkyl group,
morpholinyl-lower alkyl group or piperazinyl-lower alkyl group. The
groups may contain a hetero atom in the above chain and also may
form a ring or branch.
[0083] Aryl groups and heteroaryl groups represented by C are
either substituted or unsubstituted. Their substituents are those
listed above for R.sup.1 to R.sup.5 in the general formula
(1').
[0084] Aryl lower-alkyl groups, aryl lower-alkylamino groups, aryl
lower-alkylthio groups, aryl lower-alkoxy groups, heteroaryl
lower-alkyl groups, heteroaryl lower-alkylamino groups, heteroaryl
lower-alkylthio groups and heteroaryl lower-alkoxy represented by C
include 3-phenylpropyl group, 2-phenylethylamino group,
2-phenylethoxy group, 3-(pyridine-2-yl)propyl group,
2-(pyridine-3-yl)ethylamino group, 2-(pyridine-2-yl)ethoxy group
and the like.
[0085] Amino groups in amino lower-alkyl groups, amino
lower-alkylamino groups, amino lower-alkylthio groups and amino
lower-alkoxy groups represented by C may combine with cyclic
aliphatic amine or may contain a hetero atom in the ring thereof.
The ring herein indicates 3- to 8-membered ring and its examples
are piperidine-1-yl, piperidine-4-yl, pyrrolidine-1-yl,
pyrrolidine-3-yl, piperidinone-1-yl, pyrrolidinone-1-yl,
piperazine-1-yl and morpholine-4-yl group. Their substituents are,
for example, 2-(piperidine-1-yl)ethyl group,
2-(piperidine-1-yl)ethylamino group, 2-(piperidine-1-yl)ethylthio
group, 2-(piperidine-1-yl)ethoxy group, aminoethyl group,
aminoethylamino group, aminoethylthio group and aminoethoxy
group.
[0086] Group C in the general formula (1) is preferably a
lower-alkyl group, a lower-alkylamino group, a lower alkylthio
group or a lower-alkoxy group, and more preferably ethyl groups,
propyl groups or methylthio groups.
[0087] K represented by the general formula (3) in the groups
represented by E in the above general formula (1') represents a
hydrogen atom, a halogen atom, hydroxyl group, carboxyl group,
amino group, cyano group, nitro group or azido group. K is
preferably a hydrogen atom, hydroxyl group, carboxyl group or amino
group.
[0088] The group represented by R.sup.6 or R.sup.7 in the groups
represented by the general formula (4) in the groups represented by
E in the above general formula (1) each represent a hydrogen atom,
a linear, branched or cyclic, saturated or unsaturated hydrocarbon
group having 1 to 6 carbon atoms, a substituted or unsubstituted
aryl group, a substituted or unsubstituted heteroaryl group, a
hydroxy-lower alkyl group, a hydroxy-lower alkenyl group, a
halogeno-lower alkyl group, a halogeno-lower alkenyl group, an
aryl-lower alkyl group, an aryl-lower alkenyl group, a
heteroaryl-lower alkyl group, a heteroaryl-lower alkenyl group, a
cyano-lower alkyl group or a cyano-lower alkenyl group, and the
chains may contain a hetero atom thereof, or R.sup.6 and R.sup.7
may together form a ring which may contain a hetero atom thereof
The linear, branched or cyclic, saturated or unsaturated
hydrocarbon group having 1 to 6 carbon atoms herein include, for
example, methyl group, ethyl group, propyl group, isopropyl group,
cyclopentyl group, cyclohexyl group, allyl group and vinyl group.
Methyl group, ethyl group and the like are preferred. The
substituents in the substituted or unsubstituted aryl groups or
substituted or unsubstituted heteroaryl groups represented by
R.sup.6 or R.sup.7 are those described above with reference to
R.sup.1 to R.sup.5 in the general formula (1').
[0089] R.sup.6 and R.sup.7 may be bonded together to form a ring
with G. The ring may contain a hetero atom. The rings herein are 3-
to 8-membered rings such as cyclopentyl group, cyclohexyl group,
piperidine-1-yl group, piperidine-4-yl group, pyrrolidine-1-yl
group, pyrrolidine-3-yl group, piperidinone-1-yl group
pyrrolidinone-1-yl group, piperazine-1-yl group and morpholine-4-yl
group.
[0090] Group E in the general formula (1') is preferably a lower
alkyl group, methoxymethyl group, 2-aminoethoxymethyl group,
2-hydroxyethoxymethyl group, 2-carboxyethoxymethyl group, or a
group of the general formula (3). Group E is particularly
preferably methyl group, or a group of the general formula (4)
wherein X.sub.2 represents an oxygen atom, n represents an integer
of 2 or 3 and R.sup.6 and R.sup.7 are bonded together to form a 5-
to 7-membered ring with G (G is preferably N or C--H), such as
2-cyclohexylethoxymethyl group or 2-piperidino-ethoxymethyl
group.
[0091] Group F is preferably a group of the general formula
(5).
[0092] Group X.sub.3 include a group of the general formula (7) or
(8).
[0093] Group Y is preferably a group of the general formula (6)
wherein m represents an integer of 1 or 4 and R.sup.15 represents
an aryl group, or a saturated or unsaturated hydrocarbon group
having 3 to 4 carbon atoms. Particularly, 3-phenylpropyl group or
3-phenyl-2-propen-1-yl group is preferred.
[0094] It is preferred in the present invention represented by the
general formula (1') that A represents a group of the general
formula (2), F represents a group of the general formula (5),
X.sub.3 represents a group of the general formula (7) or (8) and Y
represents a group of the general formula (6) wherein m represents
an integer of 1 to 4, and R.sup.15 represents a substituted or
unsubstituted aryl group, or a saturated or unsaturated hydrocarbon
group having 2 to 4 carbon atoms.
[0095] Next, the explanation on the compounds represented by the
general formula (1") is given below. R.sup.16, R.sup.17, R.sup.18,
R.sup.19 and R.sup.20 of the general formula (9) represented by A'
in the above general formula (1") may be the same or different from
each other and each represents a hydrogen atom, a halogen atom,
hydroxyl group, carboxyl group, amino group, cyano group, nitro
group, a lower alkyl group, a lower alkoxyl group or a lower
alkylamino group. A lower alkyl group, a lower alkoxyl group and a
lower alkylamino group may contain a hetero atom in the chain
thereof.
[0096] B' in the above general formula (1") represents a hydrogen
atom only when Y' represents the general formula (12) and R.sup.26
is a substituted or unsubstituted aryl group, a carboxyl group only
when Y' represents the general formula (12) or Y' and F' together
form the following general formula (12'-1), (12'-2), (12"-1) or
(12"-2), or the general formula (10). The group of the general
formula (10) is preferable.
[0097] Group Z of the general formula (10) represented by B' in the
above general formula (1") represents a nitrogen atom, an oxygen
atom or a carbon atom, p represents an integer of 1 to 3, J
represents an unsubstituted group only when Z is an oxygen atom, a
hydrogen atom, a lower alkyl group which may contain a hetero atom
in the group thereof, a hydroxy-lower alkyl group, an amino-lower
alkyl group, a substituted or unsubstituted aryl group, a
substituted or unsubstituted aryl-lower alkyl group, a substituted
or unsubstituted heteroaryl group or a substituted or unsubstituted
heteroaryl-lower alkyl group. The substituents of a substituted or
unsubstituted aryl group or a substituted or unsubstituted
heteroaryl group represented by J are those listed above for
R.sup.1 to R.sup.5 in the general formula (1). It is particularly
preferred that Z represents a nitrogen atom and J represents a
hydrogen atom in the general formula (10).
[0098] K represented by the general formula (3) in the groups
represented by C' and E' in the above general formula (1")
represents a hydrogen atom, a halogen atom, hydroxyl group,
carboxyl group, amino group, cyano group, nitro group, azido group,
a substituted or unsubstituted aryl group or a substituted or
unsubstituted heteroaryl group. A hydrogen atom, hydroxyl group, a
substituted or unsubstituted aryl group or a substituted or
unsubstituted heteroaryl group is more preferable. The substituents
of a substituted or unsubstituted aryl group or a substituted or
unsubstituted heteroaryl group are those listed above for R.sup.1
to R.sup.5 in the general formula (1).
[0099] The group represented by R.sup.6 or R.sup.7 in the groups
represented by the general formula (4) in the groups represented by
C' and E' in the above general formula (1") each represent a
hydrogen atom, a linear, branched or cyclic, saturated or
unsaturated hydrocarbon group having 1 to 6 carbon atoms, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted heteroaryl group, a hydroxy-lower alkyl group, a
hydroxy-lower alkenyl group, a halogeno-lower alkyl group, a
halogeno-lower alkenyl group, an aryl-lower alkyl group, an
aryl-lower alkenyl group, a heteroaryl-lower alkyl group, a
heteroaryl-lower alkenyl group, a cyano-lower alkyl group or a
cyano-lower alkenyl group, and the chains may contain a hetero atom
thereof, or R.sup.6 and R.sup.7 may together form a ring which may
contain a hetero atom thereof. The linear, branched or cyclic,
saturated or unsaturated hydrocarbon group having 1 to 6 carbon
atoms herein include, for example, methyl group, ethyl group,
propyl group, isopropyl group, cyclopentyl group, cyclohexyl group,
allyl group and vinyl group. Methyl group, ethyl group and the like
are preferred. The substituents in the substituted or unsubstituted
aryl groups or substituted or unsubstituted heteroaryl groups
represented by R.sup.6 or R.sup.7 are those described above with
reference to R.sup.1 to R.sup.5 in the general formula (1).
[0100] R.sup.6 and R.sup.7 may be bonded together to form a ring
with G. The ring may contain a hetero atom. The rings herein are 3-
to 8-membered rings such as cyclopentyl group, cyclohexyl group,
piperidine-1-yl group, piperidine-4-yl group, pyrrolidine-1-yl
group, pyrrolidine-3-yl group, piperidinone-1-yl group
pyrrolidinone-1-yl group, piperazine-1-yl group and morpholine-4-yl
group.
[0101] C' and E' in the above general formula (1") may be the same
or different from each other and each represents a hydrogen atom, a
lower alkyl group which may contain a hetero atom in the chain
thereof, dimethoxymethyl group, cyano group, a hydroxy-lower alkyl
group or a halogeno-lower alkyl group. A lower alkyl group is
particularly preferable.
[0102] R.sup.21, R.sup.22, R.sup.23, R.sup.24 and R.sup.25 of the
general formula (11) represented by F' in the above general formula
(1") may be the same or different from each other and each
represents a hydrogen atom, a halogen atom, hydroxyl group,
carboxyl group, amino group, cyano group, nitro group, a lower
alkyl group, a lower alkoxyl group, a lower alkylamino group, a
substituted or unsubstituted aryl group or a substituted or
unsubstituted heteroaryl group. The substituents in the substituted
or unsubstituted aryl groups or substituted or unsubstituted
heteroaryl groups represented by R.sup.21 to R.sup.25 are those
described above with reference to R.sup.1 to R.sup.5 in the general
formula (1).
[0103] The groups represented by X' are an oxygen atom or
>NH.
[0104] The groups represented by Y' are preferably a group of the
general formula (12) wherein h represents an integer of 1 to 4 and
R.sup.26 represents an aryl group, or a saturated or unsaturated
hydrocarbon group having 3 to 4 carbon atoms. Particularly,
3,3-diphenylpropyl group is preferable.
[0105] Y' and F' may together form a group of the general formula
(12'-1), (12'-2), (12"-1) or (12"-2).
[0106] Further, it is preferable in the present invention
represented by the general formula (1") that B' represents a group
of the general formula (10).
[0107] It is preferable in the present invention that B' represents
a group of the general formula (10), Y represents a group of the
general formula (12) and X' represents an oxygen atom.
[0108] It is preferable in the present invention that B' represents
carboxyl groups and E' represents a group of the general formula
(3) or (4).
[0109] It is preferable in the present invention that B' represents
carboxyl groups, E' represents a group of the general formula (3)
or (4), X' represents an oxygen atom and Y' represents a group of
the general formula (12).
[0110] It is preferable in the present invention that C' and E' may
be the same or different from each other and each represents a
hydrogen atom, a lower alkyl group which may contain a hetero atom
in the chain thereof, dimethoxymethyl group, cyano group, a
hydroxy-lower alkyl group or a halogeno-lower alkyl group, and B'
represents a group of the general formula (10).
[0111] It is preferable in the present invention that B' represents
a group of the general formula (10) wherein Z represents a nitrogen
atom and J represents a hydrogen atom, C' and E' represent a lower
alkyl group, and Y' represents a group of the general formula (12)
wherein R.sup.26 represents a substituted or unsubstituted aryl
group and h=2.
[0112] It is preferable in the present invention that B' represents
a group of the general formula (10) wherein Z represents a nitrogen
atom and J represents a hydrogen atom, C' and E' represent a lower
alkyl group, Y' represents a group of the general formula (12)
wherein R.sup.26 represents a substituted or unsubstituted aryl
group and h=2, and X' represents an oxygen atom.
[0113] The compounds of the present invention represented by the
general formula (1") are preferably those wherein A' represents
3-chlorophenyl group, B' represents a carboxyl group, C' and E'
represent a methyl group, X' represents an oxygen atom, Y' and F'
together form a group of the general formula (12"-1), i represents
an integer of 3 and R.sup.32, R.sup.33, R.sup.34 and R.sup.35
represent a hydrogen atom, and pharmaceutically acceptable salts
thereof.
[0114] Pyrimidine derivatives and pyridine derivatives of the
present invention can be produced by processes described below:
[0115] <Production Process 1>
[0116] The pyrimidine derivatives (1) of the present invention can
be produced by a method described below.
[0117] For example, the pyrimidine derivative (1-1) of the general
formula (1) wherein E is methyl group and X.sub.1 is
>N--R.sub.14, in which R.sub.14 is hydrogen atom, can be
produced by the following process: 20
[0118] The .beta.-ketocarboxylic acid amide (15) can be obtained by
reacting the diketene dimer (13) with the amine derivative (14) in
the presence of a base such as triethylamine. As the reaction
solvent, aromatic hydrocarbons such as toluene, benzene or xylene
can be used. The reaction temperature is 0 to 150.degree. C.,
preferably 50 to 120.degree. C.
[0119] The pyrimidine derivative (1-1) can be obtained by reacting
the .alpha., .beta.-unsaturated carbonyl compound (17), obtained by
the dehydration condensation of the .beta.-ketocarboxylic acid
amide (15) with the aldehyde (16), with the amidine derivative
(18).
[0120] When the amidine derivative used herein is in the form of
hydrochloride or the like, it is preferably converted into the free
amine with a base such as potassium carbonate, sodium acetate or
sodium hydrogencarbonate. The reaction solvents include aprotic
polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide
and acetonitrile. The reaction temperature is not particularly
limited, and the reaction can be carried out under cooling, at room
temperature or under heating.
[0121] By this reaction, a dihydropyrimidine derivative (19) of the
following formula, wherein A and R.sub.27 are as defined above,
might be produced according to the reaction conditions. In such a
case, the intended pyrimidine derivative (1-1) can be obtained by
the oxidation reaction of the dihydropyrimidine derivative (19).
The oxidizing agents usable for the oxidation reaction include, for
example, manganese dioxide, lead tetraacetate, oxygen, hydrogen
peroxide, potassium permanganate, DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and CAN (cerium
diammonium nitrate). The reaction is usually carried out in an
ordinary solvent that is inert to the reaction, such as chloroform,
methylene chloride, benzene, toluene, pyridine, ethyl acetate,
acetone or methyl ethyl ketone. The reaction temperature is not
particularly limited, and the reaction is preferably carried out at
room temperature or under warming or heating. 21
[0122] <Production Process 2>
[0123] The pyrimidine derivatives (1') of the present invention can
be produced by a method described below.
[0124] For example, the pyrimidine derivative (1'-1) of the general
formula (1') wherein E is methyl group and X.sub.3 is represented
by the general formula (8) can be produced by the following
process: 22
[0125] The acetoacetic acid ester derivative (22) can be obtained
by the transesterification of the methyl acetoacetate (20) with the
alcohol (21). As the reaction solvent, aromatic hydrocarbons such
as benzene, toluene or xylene are usually used. However, the
intended product can also be obtained by reacting the substrate
with the alcohol without any reaction solvent. The reaction
temperature is usually 50 to 150.degree. C.
[0126] The dihydropyrimidine derivative (24) can be obtained by
reacting the .alpha., .beta.-unsaturated carbonyl compound (23),
obtained by the dehydration condensation of the acetoacetic acid
ester derivative (22) with the aldehyde (16), with the amidine
derivative (18).
[0127] When the amidine derivative used herein is in the form of
hydrochloride or the like, it is preferably converted into the free
amine with a base such as potassium carbonate, sodium acetate or
sodium hydrogencarbonate. The reaction solvents include aprotic
polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide
and acetonitrile. The reaction temperature is not particularly
limited, and the reaction can be carried out under cooling, at room
temperature or under heating.
[0128] The intended pyrimidine derivative (1'-1) can be obtained by
the oxidation reaction of the dihydropyrimidine derivative (24)
with a suitable oxidizing agent. The oxidizing agents usable for
the oxidation reaction include, for example, manganese dioxide,
lead tetraacetate, oxygen, hydrogen peroxide, potassium
permanganate, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and
CAN (cerium diammonium nitrate). The reaction is usually carried
out in an ordinary solvent that is inert to the reaction, such as
chloroform, methylene chloride, benzene, toluene, pyridine, ethyl
acetate, acetone or methyl ethyl ketone. The reaction temperature
is not particularly limited, and the reaction is preferably carried
out at room temperature or under warming or heating.
[0129] <Production Process 3>
[0130] The pyrimidine derivatives (1') of the present invention can
be produced by a method described below.
[0131] For example, the pyrimidine derivative (1'-2) of the general
formula (1') wherein E is represented by the general formula (3) or
(4), in which X.sub.2 is an oxygen atom, and X.sub.3 is represented
by the general formula (8) can be produced by the following
process: 23
[0132] Namely, the methyl .beta.-ketocarboxylate derivative (27)
can be obtained by reacting an alkoxide, produced from the alcohol
(26) and a base such as potassium carbonate, sodium carbonate or
sodium hydride, and commercially available methyl
4-chloroacetoacetate (25). The reaction solvents include aprotic
polar solvents such as tetrahydrofuran, N,N-dimethylformamide,
dimethyl sulfoxide and acetonitrile. The reaction temperature is
not particularly limited, and the reaction can be carried out under
cooling, at room temperature or under heating. Then the methyl
.beta.-ketocarboxylate derivative (27) is transesterified with the
alcohol (21) to obtain the .beta.-ketocarboxylate derivative (28).
Aromatic hydrocarbons such as benzene, toluene or xylene are
usually used as the reaction solvent. However, the intended product
can also be obtained by reacting the substrate with the alcohol
without any reaction solvent. The reaction temperature is usually
50 to 150.degree. C.
[0133] The dihydropyrimidine derivative (30) can be obtained by
reacting the .alpha., .beta.-unsaturated carbonyl compound (29),
obtained by the dehydration condensation of the methyl
.beta.-ketocarboxylate derivative (28) with the aldehyde (16), with
the amidine derivative (18).
[0134] When the amidine derivative used herein is in the form of
hydrochloride or the like, it is preferably converted into the free
amine with a base such as potassium carbonate, sodium acetate or
sodium hydrogencarbonate. Aprotic polar solvents such as
N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile can be
used as the reaction solvent. Although the reaction temperature is
not particularly limited, the reaction can be carried out under
cooling, at room temperature or under heating.
[0135] The intended pyrimidine derivative (1'-2) can be obtained by
the oxidation reaction of the dihydropyrimidine derivative (30)
with a suitable oxidizing agent. The oxidizing agents usable for
the oxidation reaction include, for example, manganese dioxide,
lead tetraacetate, oxygen, hydrogen peroxide, potassium
permanganate, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and
CAN (cerium diammonium nitrate). The reaction is usually carried
out in an ordinary solvent that is inert to the reaction, such as
chloroform, methylene chloride, benzene, toluene, pyridine, ethyl
acetate, acetone or methyl ethyl ketone. Although the reaction
temperature is not particularly limited, the reaction is preferably
carried out at room temperature or under warming or heating.
[0136] <Production Process 4>
[0137] The pyrimidine derivatives (1') of the present invention can
be produced by a method described below.
[0138] For example, the pyrimidine derivative (1'-3) of the general
formula (1'), wherein E is methyl group and X.sub.3 is represented
by the general formula (7), can be produced by the following
process: 24
[0139] The dihydropyrimidine derivative (33) can be obtained by
reacting the .alpha., .beta.-unsaturated carbonyl compound (32),
obtained by the dehydration condensation of the ethyl acetoacetate
(31) with the aldehyde (16), with the amidine derivative (18).
[0140] When the amidine derivative used herein is in the form of
hydrochloride or the like, it is preferably converted into the free
amine with a base such as potassium carbonate, sodium acetate or
sodium hydrogencarbonate. Aprotic polar solvents such as
N,N-dimethylformamide, dimethyl sulfoxide and acetonitrile can be
used as the reaction solvent. The reaction temperature is not
particularly limited, and the reaction can be carried out under
cooling, at room temperature or under heating.
[0141] The pyrimidine derivative (34) can be obtained by the
oxidation reaction of the dihydropyrimidine derivative (33) with a
suitable oxidizing agent. The oxidizing agents usable for the
oxidation reaction include, for example, manganese dioxide, lead
tetraacetate, oxygen, hydrogen peroxide, potassium permanganate,
DDQ (2,3-dichloro-5,6-dicyano-- 1,4-benzoquinone) and CAN (cerium
diammonium nitrate). The reaction is usually carried out in an
ordinary solvent that is inert to the reaction, such as chloroform,
methylene chloride, benzene, toluene, pyridine, ethyl acetate,
acetone or methyl ethyl ketone. Although the reaction temperature
is not particularly limited, the reaction is preferably carried out
at room temperature or under warming or heating.
[0142] The obtained pyrimidine derivative (34) is treated with a
base such as sodium hydroxide, potassium hydroxide or lithium
hydroxide to obtain the carboxylic acid derivative (35). This
carboxylic acid derivative (35) is subjected to Crutius
rearrangement with diphenylphosphoric azide (DPPA) in the presence
of a base such as triethylamine and an alcohol such as t-butyl
alcohol to obtain the corresponding carbamate derivative (37).
Although a protic polar solvent other than t-butyl alcohol can be
used as the reaction solvent, t-butyl alcohol or benzyl alcohol is
preferred in view of the removal of the protecting group in the
subsequent step. The reaction is usually carried out under heating
at 50 to 150.degree. C.
[0143] The protecting group is removed from the obtained carbamate
derivative (37) to obtain the amine derivative (38), that is then
reacted with the corresponding acyl chloride (39) in the presence
of a base such as pyridine or triethylamine to obtain the intended
pyrimidine derivative (1'-3). When the carbamate derivative (37) is
t-butyl carbamate, it is reacted with an acid such as hydrochloric
acid or trifluoroacetic acid. When the carbamate derivative (37) is
benzyl carbamate, it is catalytically reduced with palladium carbon
to obtain the corresponding amine derivative (38). When the acyl
chloride (39) is not available on the market, a corresponding
carboxylic acid is reacted with a chlorinating agent such as oxalyl
chloride or thionyl chloride to obtain the acyl chloride (39). The
reaction of the acyl chloride (39) with the amine derivative (38)
is carried out in an ordinary solvent inert to the reaction, such
as chloroform, methylene chloride, tetrahydrofuran, benzene or
toluene. Although the reaction temperature is not particularly
limited, the reaction is preferably carried out at room temperature
or under warming or heating. The intended pyrimidine derivative
(1'-3) can also be synthesized by condensing the amine derivative
(38) with a corresponding carboxylic acid in the presence of a
condensing agent such as WSC,
[0144] <Production Process 5>
[0145] The pyridine derivatives (1") of the present invention can
be produced by a method described below.
[0146] The pyridine derivative (1"-1) of the general formula (1"),
wherein B' is represented by the general formula (10), C and E are
each methyl group and X' is oxygen atom, can be produced by the
following process: 25
[0147] The dihydropyridinecarboxylic acid diester (42) can be
obtained by reacting the aldehyde (16), 3-aminocrotonic acid ester
(40) and the .beta.-ketocarboxylic acid ester (41). As the reaction
solvent, a protic polar solvent such as ethanol or 2-propanol can
be used. The reaction temperature is 0 to 150.degree. C.,
preferably 50 to 120.degree. C.
[0148] The dihydropyridinecarboxylic acid diester (42) thus
obtained is treated with a base such as sodium hydroxide to obtain
a dihydropyridine monocarboxylic acid (43), that is then condensed
with the amine derivative (44) in the presence of a condensing
agent such as WSC to obtain the dihydropyridine amide derivative
(45).
[0149] The dihydropyridine amide derivative (45) thus obtained is
subjected to the oxidation reaction to obtain the intended pyridine
derivative (1"-1). The oxidizing agents usable for the oxidation
reaction include, for example, manganese dioxide, lead
tetraacetate, oxygen, hydrogen peroxide, potassium permanganate,
DDQ (2,3-dichloro-5,6-dicyano-- 1,4-benzoquinone) and CAN (cerium
diammonium nitrate). The reaction is usually carried out in an
ordinary solvent that is inert to the reaction, such as chloroform,
methylene chloride, benzene, toluene, pyridine, ethyl acetate,
acetone or methyl ethyl ketone. Although the reaction temperature
is not particularly limited, the reaction is preferably carried out
at room temperature or under warming or heating.
[0150] <Production Process 6>
[0151] The pyridine derivatives (1"-1) of the present invention can
be produced by a method shown below. 26
[0152] The dihydropyridinecarboxylic acid diester (42) can be
obtained by producing the a .beta.-unsaturated carbonyl compound
(46) by the dehydration condensation of the .beta.-ketocarboxylic
acid ester (41) with the aldehyde (16) and then reacting this
product with the 3-aminocrotonic acid ester (40). The intended
pyridine derivative (1"-1) can be produced from the obtained
dihydropyridinecarboxylic acid diester (42) by the production
process 5.
[0153] <Production Process 7>
[0154] The pyridine derivatives (1"-1) can also be produced by a
method shown below. 27
[0155] The .beta.-ketocarboxylic acid amide (47) can be obtained by
reacting the diketene dimer (13) with the amine derivative (44) in
the presence of a base such as triethylamine. As the reaction
solvent, aromatic hydrocarbons such as toluene, benzene or xylene
can be used. The reaction temperature is 0 to 150.degree. C.,
preferably 50 to 120.degree. C. The dihydropyridipecarboxylic acid
diester (49) can he obtained by producing the .alpha.,
.beta.-unsaturated carbonyl compound (48) by the dehydration
condensation of the .beta.-ketocarboxylic acid amide (47) with the
aldehyde (16) and then reacting this compound with the
3-aminocrotonic acid ester (40). As the reaction solvent, a protic
polar solvent such as ethanol or 2-propanol can be used. The
reaction temperature is not particularly limited, and the reaction
is preferably carried out at room temperature or under warming or
heating.
[0156] The dihydropyridinemonocarboxylic acid (50) can be obtained
by treating the obtained dihydropyridinecarboxylic acid diester
(49) with a base such as sodium hydroxide. The dihydropyridine
amide derivative (52) is formed by condensing the
dihydropyridinemonocarboxylic acid (49) with the amine derivative
(51) in the presence of a condensing agent such as WSC.
[0157] The intended pyridine derivative (1"-1) can be obtained by
subjecting the resultant dihydropyridine amide derivative (52) to
the oxidation reaction. The oxidizing agent used for the oxidation
reaction include, for example, manganese dioxide, lead
tetraacetate, oxygen, hydrogen peroxide, potassium permanganate,
DDQ (2,3-dichloro-5,6-dicyano-- 1,4-benzoquinone) and CAN (cerium
diammonium nitrate). The reaction is usually carried out in an
ordinary solvent that is inert to the reaction, such as chloroform,
methylene chloride, benzene, toluene, pyridine, ethyl acetate,
acetone or methyl ethyl ketone. Although the reaction temperature
is not particularly limited, the reaction is preferably carried out
at room temperature or under warming or heating.
[0158] <Production Process 8>
[0159] The pyridine derivatives (1") of the present invention can
be produced by a method described below.
[0160] The pyridine derivative (1"-2) of the general formula (1"),
wherein B' is carboxyl group, C and E are each methyl group and X'
is oxygen atom, can be produced by the following process: 28
[0161] The dihydropyridinecarboxylic acid diester (42) can be
obtained by subjecting the .beta.-ketocarboxylic acid ester (41)
and the aldehyde (16) to the dehydration condensation and then
reacting the obtained .alpha., .beta.-unsaturated carbonyl compound
(46) with 3-aminocrotonic acid ester (40). As the reaction solvent,
a protic polar solvent such as ethanol or 2-propanol can be used.
Although the reaction temperature is not particularly limited, the
reaction is preferably carried out at room temperature or under
warming or heating.
[0162] The dihydropyridinecarboxylic acid diester (42) thus
obtained can be treated with a base such as sodium hydroxide to
obtain a dihydropyridine monocarboxylic acid (43), that is then
subjected to the oxidation reaction to obtain the intended pyridine
derivative (1"-2). The oxidizing agents usable for the oxidation
reaction include, for example, manganese dioxide, lead
tetraacetate, oxygen, hydrogen peroxide, potassium permanganate,
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and CAN (cerium
diammonium nitrate). The reaction is usually carried out in an
ordinary solvent that is inert to the reaction, such as chloroform,
methylene chloride, benzene, toluene, pyridine, ethyl acetate,
acetone or methyl ethyl ketone. The reaction temperature is not
particularly limited, and the reaction is preferably carried out at
room temperature or under warming or heating.
[0163] <Production Process 9>
[0164] The pyridine derivatives (1") of the present invention can
be produced by a method described below.
[0165] The pyridine derivative (1"-3) of the general formula (1"),
wherein B' is represented by the general formula (10), C is methyl
group, E is represented by the general formula (3) or (4), wherein
X.sub.2 is oxygen atom, and X' is oxygen atom, can be produced by
the following process: 2930
[0166] Namely, the methyl .beta.-ketocarboxylate derivative (27)
can be obtained by reacting an alkoxide produced from the alcohol
(26) and a base such as potassium carbonate, sodium carbonate or
sodium hydride with commercially available methyl
4-chloroacetoacetate (25). The reaction solvents include aprotic
polar solvents such as tetrahydrofuran, N,N-dimethylformamide,
dimethyl sulfoxide and acetonitrile. The reaction temperature is
not particularly limited, and the reaction can be carried out under
cooling, at room temperature or under heating. Then the methyl
.beta.-ketocarboxylate derivative (27) is transesterified with the
alcohol (53) to obtain the .beta.-ketocarboxylate derivative (54).
Aromatic hydrocarbons such as benzene, toluene or xylene are
usually used as the reaction solvent. However, the intended product
can also be obtained by reacting the substrate with the alcohol
without any reaction solvent. The reaction temperature is usually
50 to 150.degree. C.
[0167] The dihydropyridine carboxylic acid diester (56) can be
obtained by reacting the .alpha., .beta.-unsaturated carbonyl
compound (55), obtained by the dehydration condensation of the
8-ketocarboxylate derivative (54) with the aldehyde (16), with the
3-aminocrotonic acid ester (40). As for the reaction solvent, a
protic polar solvent such as ethanol or 2-propanol can be used. The
reaction temperature is not particularly limited, and the reaction
is preferably carried out at room temperature or under warming or
heating.
[0168] The dihydropyridinemonocarboxylic acid (57) can be obtained
by treating the dihydropyridinecarboxylic acid diester (56) with a
base such as sodium hydroxide. The dihydropyridine amide derivative
(58) is formed by condensing the dihydropyridinemonocarboxylic acid
(57) with the amine derivative (44) in the presence of a condensing
agent such as WSC. The intended pyridine derivative (1"-3) can be
obtained by the oxidation reaction of the dihydropyridine amide
derivative (58). The oxidizing agents usable for the oxidation
reaction include, for example, manganese dioxide, lead
tetraacetate, oxygen, hydrogen peroxide, potassium permanganate,
DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and CAN (cerium
diammonium nitrate). The reaction is usually carried out in an
ordinary solvent that is inert to the reaction, such as chloroform,
methylene chloride, benzene, toluene, pyridine, ethyl acetate,
acetone or methyl ethyl ketone. The reaction temperature is not
particularly limited, and the reaction is preferably carried out at
room temperature or under warming or heating.
[0169] When the compounds of general formulae (1), (1') and (1")
can form salts thereof, the salts are pharmaceutically acceptable
ones such as ammonium salts, salts thereof with alkali metals, e.
g. sodium and potassium, salts thereof with alkaline earth metals,
e. g. calcium and magnesium, salts thereof with aluminum and zinc,
salts thereof with organic amines, e. g. morpholine and piperidine,
and salts thereof with basic amino acids, e. g. arginine and
lysine.
[0170] The compounds of general formulae (1), (1') and (1") and
salts thereof can be administered as they are or in the form of
various medicinal compositions to patients. The dosage forms of the
medicinal compositions are, for example, tablets, powders, pills,
granules, capsules, suppositories, solutions, sugar-coated tablets
and depots. They can be prepared with ordinary preparation
assistants by an ordinary method. For example, the tablets can be
prepared by mixing the pyrimidine derivative, the active ingredient
of the present invention, with any of known adjuvants such as inert
diluents, e. g. lactose, calcium carbonate and calcium phosphate;
binders, e. g. acacia, corn starch and gelatin; extending agents,
e. g. alginic acid, corn starch and pre-gelatinized starch;
sweetening agents, e. g. sucrose, lactose and saccharin;
corrigents, e. g. peppermint, gaultheria leaves oil and cherry; and
lubricants, e. g. magnesium stearate, talc and carboxymethyl
cellulose.
[0171] The N-type calcium channel antagonists containing one of the
compounds of above general formulae (1), (1') and (1") or one of
salts thereof as active ingredient is usable as a therapeutic agent
for various diseases, for example, acute stage of ischemic
cerebrovascular disorders such as cerebral infarction or
intracerebral bleeding (including subarachnoidal hemorrhage);
progressive neurodegenerative diseases such as Alzheimer's disease,
AIDS related dementia, Parkinson's disease, dementia due to
cerebrovascular disorder and ALS; neuropathy caused by head injury;
various pains such as pain caused by spinal injury, diabetes or
thromboangiitis obliterans, neurogenic pain, migraine, visceral
pain and cancerous pain; various diseases associated with
psychogenic stress such as bronchial asthma, unstable angina and
irritable colitis; withdrawal symptoms after addiction to drugs
such as emotional disorder and ethanol addiction withdrawal
symptoms.
[0172] The dose of the compound used for the above-described
purpose varies depending on the intended therapeutic effect,
administration method, period of the treatment, and age and body
weight of the patient. The dose is usually 1 .mu.g to 5 g a day for
adults in the oral administration, and 0.01 .mu.g to 1 g a day for
adults in the parenteral administration.
[0173] The following Examples will further illustrate the present
invention, which are only preferred embodiments of the invention
and which by no means limit the invention.
EXAMPLE 1
[0174] Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenyl-
-2-propen-1-yl)-5-pyrimidinecarboxamide:
[0175] 1) Synthesis of 3-oxo-N-(3-phenyl-2-propen-1-yl)
butylamide:
[0176] 3.06 g (23.0 mmol) of cinnamyl amine, 2.32 ml (30.1 mmol) of
diketene and 0.321 ml (2.30 mmol) of triethylamine were heated and
stirred in 50 ml of toluene at 70.degree. C. for 3 hours. After
saturated aqueous sodium hydrogencarbonate solution was added, the
reaction mixture was extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate and concentrated
under reduced pressure to obtain the title compound.
[0177] Yield: 5.08 g (23.4 mmol) (quantitative yield)
[0178] MS (ESI, m/z) 216 (M-H).sup.-
[0179] .sup.1H-NMR (CDCl3): 2.29 (3H, s), 3.47 (2H, s), 4.07 (2H,
t), 6.20 (1H, dt), 6.54 (1H, d), 7.15-7.40 (5H, m).
[0180] 2) Synthesis of
2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propen-1-- yl)
acrylamide:
[0181] 30.0 mg (1.38 mmol) of 3-oxo-N-(3-phenyl-2-propen-1-yl)
butylamide and 194 mg (1.38 mmol) of 3-chlorobenzaldehyde were
dissolved in 20 ml of 2-propanol. 4.14 mg (0.0690 mmol) of
piperidine and 5.67 mg (0.0690 mmol) of acetic acid were added
thereto and-stirred at room temperature for 2 days. After the
solvent was evaporated under reduced pressure, ethyl acetate was
added to the reaction mixture. After washing with 1 N hydrochloric
acid and then with saturated aqueous sodium hydrogencarbonate
solution, the organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1) to obtain the title compound.
[0182] Yield: 413 mg (1.21 mmol) (88%)
[0183] MS (ESI, m/z) 340 (M+H).sup.+
[0184] .sup.1H-NMR (CDCl3): 2.43 (3H, s), 4.10-4.16 (2H, m),
6.05-6.17 (2H, m), 6.70 (1H, d), 7.22-7.32 (7H, m), 7.41-7.45 (2H,
m), 7.52 (1H, s).
[0185] 3) Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phe-
nyl-2-propen-1-yl)-5-pyrimidinecarboxamide:
[0186] 413 mg (1.21 mmol) of
2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-pro- pen-1-yl) acrylamide
was dissolved in 10 ml of DMF. 269 mg (0.968 mmol) of
methylisothiourea-sulfate and 149 mg of (1.82 mmol) of sodium
acetate were added thereto at room temperature and stirred at
100.degree. C. for 2 days. DMF was evaporated under reduced
pressure, and the residue was diluted with ethyl acetate and washed
with saturated aqueous sodium chloride solution. The organic layer
was dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by the silica gel
chromatography (hexane/ethyl acetate=10/1) to obtain the title
compound.
[0187] Yield: 156 mg(0.379mmol)(31%)
[0188] MS (ESI, m/z) 410 (M+H).sup.+
[0189] .sup.1H-NMR (CDCl3): 2.58 (3H, s), 2.61 (3H, s), 4.04 (2H,
t), 5.52 (1H, br t), 5.89 (1H, dt), 6.31 (1H, d), 7.23-7.40 (7H,
m), 7.65-7.68 (1H, m), 7.82 (1H, t).
EXAMPLE 2
[0190] Synthesis of
4-(3-chlorophenyl)-N-(3,3-diphenylpropyl)-6-methyl-2-(-
methylthio)-5-pyrimidinecarboxamide:
[0191] The title compound was obtained by using 157 mg (0.376 mmol)
of 2-acetyl-3-(3-chlorophenyl)-N-(3,3-diphenylpropyl) acrylamide,
83.8 mg (0.301 mmol) of methylisothiourea-sulfate and 37.0 mg
(0.451 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0192] Yield: 49.8 mg (0.102 mmol) (27%)
[0193] MS (ESI, m/z) 488 (M+H).sup.+
[0194] .sup.1H-NMR (CDCl3): 2.06-2.13 (2H, m), 2.52 (3H, s), 2.61
(3H, s), 3.22 (2H, q) 3.66 (1H, t), 5.35 (1H,br t), 7.09-7.38 (12H,
m), 7.65 (1H, dt), 7.80 (1H, t).
EXAMPLE 3
[0195] Synthesis of
4-(3-chlorophenyl)-6-methyl-N-(3-phenyl-2-propen-1-yl)-
-2-(pyridine-3-yl)-5-pyrimidinecarboxamide:
[0196] 100 mg (0.294 mmol) of
2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-pr- open-1-yl) acrylamide
was dissolved in 5 ml of DMF. 60.1 mg (0.381 mmol) of
3-amidinopyridinium hydrochloride and 28.9 mg of (0.353 mmol) of
sodium acetate were added thereto and stirred at room temperature
overnight. The reaction mixture was diluted with ethyl acetate and
washed with saturated aqueous sodium chloride solution. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The obtained residue was
stirred at 120.degree. C. overnight, cooled down at room
temperature and purified by the silica gel chromatography
(hexane/ethyl acetate=1/2) to obtain the title compound.
[0197] Yield: 21.8 mg (0.0494 mmol) (17%)
[0198] MS (ESI, m/z) 441 (M+H).sup.+, 439 (M-H).sup.-
[0199] .sup.1H-NMR (CDCl3): 2.74 (3H, s), 4.13 (2H, t), 5.95-6.05
(1H, m), 6.37 (1H, d), 7.07 (1H, s), 7.23-7.47 (8H, m), 7.78 (1H,
dd), 7.85 (1H, s), 8.50 (1H, d), 8.65 (1H, t), 9.34 (1H, s).
EXAMPLE 4
[0200] Synthesis of
4-(3-chlorophenyl)-6-methyl-2-phenyl-N-(3-phenyl-2-pro-
pen-1-yl)-5-pyrimidinecarboxamide:
[0201] The title compound was obtained by using 120 mg (0.353 mmol)
of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propen-1-yl)
acrylamide, 83.4 mg (0.530 mmol) of benzamidine hydrochloride and
43.5 mg (0.530 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0202] Yield: 42.0 mg (0.0950 mmol) (27%)
[0203] MS (ESI, m/z) 440 (M+H).sup.+, 438 (M-H).sup.-
[0204] .sup.1H-NMR (CDCl3): 2.70 (3H, s), 4.07 (2H, t), 5.65 (1H,
s), 5.87-5.97 (1H, m), 6.32 (1H, d), 7.22-7.42 (7H, m), 7.45-7.52
(3H, m), 7.76 (1H, dd), 7.95 (1H, s), 8.51-8.54 (2H, m).
EXAMPLE 5
[0205] Synthesis of
4-(3-chlorophenyl)-N-(3,3-diphenylpropyl)-6-methyl-2-(-
pyridine-3-yl)-5-pyrimidinecarboxamide:
[0206] The title compound was obtained by using 167 mg (0.400 mmol)
of 2-acetyl-3-(3-chlorophenyl)-N-(3,3-diphenylpropyl) acrylamide,
94.5 mg (0.599 mmol) of 3-amidinopyridinium hydrochloride and 49.1
mg (0.599 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0207] Yield: 72.0 mg (0.138 mmol) (35%)
[0208] MS (ESI, m/z) 519 (M+H).sup.+
[0209] .sup.1H-NMR (CDCl3): 2.20 (2H, q), 2.68 (3H, s), 3.32 (2H,
q), 3.79 (1H, t), 7.13-7.40 (13H, m), 7.76 (1H, dt), 7.83 (1H, t),
8.45 (1H, dd), 8.63 (1H, dt), 9.25 (1H, d).
EXAMPLE 6
[0210] Synthesis of
4-(3,4-dichlorophenyl)-N-(3,3-diphenylpropyl)-6-methyl-
-2-(methylthio)-5-pyrimidinecarboxamide:
[0211] The title compound was obtained by using 100 mg (0.221 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3,3-diphenylpropyl)
acrylamide, 49.2 mg (0.177 mmol) of methylisothiourea-sulfate and
21.8 mg (0.265 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0212] Yield: 30.1 mg (0.0576 mmol) (26%)
[0213] MS (ESI, m/z) 522 (M+H).sup.+
[0214] .sup.1H-NMR (CDCl.sub.3): 2.13 (2H, q), 2.49 (3H, s), 2.59
(3H, s), 3.23 (2H, q), 3.75 (1H, t), 5.56 (1H, br t), 7.63 (1H,
dd), 7.93 (1H, d).
EXAMPLE 7
[0215] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0216] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
59.2 mg (0.213 mmol) of methylisothiourea-sulfate and 26.2 mg
(0.319 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0217] Yield: 22.9 mg (0.0513 mmol) (19%)
[0218] MS (ESI, m/z) 446 (M+H).sup.+
[0219] .sup.1H-NMR (CDCl3): 1.73 (2H, quint), 2.45-2.52 (5H, m),
2.59 (3H, s), 3.30 (2H, q) 5.56 (1H, br t), 7.05 (2H, d), 7.15-7.20
(1H, m), 7.24-7.29 (2H, m), 7.48 (1H, d), 7.65 (1H, dd), 7.93 (1H,
d).
EXAMPLE 8
[0220] Synthesis of
4-(3,5-dichlorophenyl)-N-(3,3-diphenylpropyl)-6-methyl-
-2-(methylthio)-5-pyrimidinecarboxamide:
[0221] The title compound was obtained by using 100 mg (0.221 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3,3-diphenylpropyl)
acrylamide, 49.2 mg (0.177 mmol) of methylisothiourea-sulfate and 2
1.8 mg (0.265 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0222] Yield: 25.8 mg (0.0494 mmol) (22%)
[0223] MS (ESI, m/z) 522 (M+H).sup.+
[0224] .sup.1H-NMR (CDCl3): 2.14 (2H, q), 2.50 (3H, s), 2.60 (3H,
s), 3.25 (2H, q), 3.69 (1H, t), 5.51 (1H, br t), 7.13-7.35 (11H,
m), 7.67 (2H, d).
EXAMPLE 9
[0225] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0226] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
59.2 mg (0.213 mmol) of methylisothiourea-sulfate and 26.2 mg
(0.319 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0227] Yield: 13.2 mg (0.0296 mmol) (11%)
[0228] MS (ESI, m/z) 446 (M+H).sup.+
[0229] .sup.1H-NMR (CDCl3): 1.74 (2H, quint), 2.48 (2H, t), 2.53
(3H, s), 2.60 (3H, s), 3.32 (2H, q), 5.53 (1H, br t), 7.07 (2H, d),
7.15-7.29 (3H, m), 7.41 (1H, t), 7.69 (2H, d).
EXAMPLE 10
[0230] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0231] The title compound was obtained by using 100 mg (0.267 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenyl-2-propen-1-yl)
acrylamide, 59.5 mg (0.214 mmol) of methylisothiourea-sulfate and
26.3 mg (0.320 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0232] Yield: 36.1 mg (0.0812 mmol) (30%)
[0233] MS (ESI, m/z) 444 (M+H).sup.+
[0234] .sup.1H-NMR (CDCl3): 2.57 (3H, s), 2.60 (3H, s), 4.07 (3H,
t), 5.64 (1H, br t), 5.96 (1H, dt), 6.36 (1H, d), 7.24-7.36 (6H,
m), 7.69 (2H, d).
EXAMPLE 11
[0235] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0236] The title compound was obtained by using 75.7 mg (0.202
mmol) of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3-phenyl-2-propen-1-yl)
acrylamide, 45.0 mg (0.162 mmol) of methylisothiourea sulfate and
19.9 mg (0.242 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0237] Yield: 22.4 mg (0.0504 mmol) (25%)
[0238] MS (ESI, m/z) 444 (M+H).sup.+
[0239] .sup.1H-NMR (CDCl3): 2.56 (3H, s), 2.60 (3H, s), 4.06 (2H,
t), 5.66 (1H, br t), 5.92 (1H, dt), 6.35 (1H, d), 7.22-7.35 (5H,
m), 7.44 (1H, d), 7.64 (1H, dd), 7.95 (1H, d).
EXAMPLE 12
[0240] Synthesis of
4-(3,5-dichlorophenyl)-2,6-dimethyl-N-(3-phenylpropyl)-
-5-pyrimidinecarboxamide:
[0241] The title compound was obtained by using 80.0 mg (0.214
mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenyl-2-propen-1-yl)
acrylamide, 30.3 mg (0.321 mmol) of acetamidine hydrochloride and
21.1 mg (0.257 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0242] Yield: 45.1 mg (0.109 mmol) (51%)
[0243] MS (ESI, m/z) 412 (M+H).sup.+
[0244] .sup.1H-NMR (CDCl3): 2.61 (3H, s), 2.75 (3H, s), 4.08 (2H,
t), 5.64 (1H, br t), 5.96 (1H, dt), 6.37 (1H, d), 7.25-7.36 (6H,
m), 7.68 (2H, d).
EXAMPLE 13
[0245] Synthesis of
4-(3-chlorophenyl)-6-methyl-2-phenyl-N-(3-phenylpropyl-
)-5-pyrimidinecarboxamide:
[0246] The title compound was obtained by using 120 mg (0.351 mmol)
of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenylpropyl) acrylamide, 82 mg
(0.525 mmol) of benzamidine hydrochloride and 34.5 mg (0.421 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0247] Yield: 28.7 mg (0.0649 mmol) (18%)
[0248] MS (ESI, m/z) 442 (M+H).sup.+
[0249] .sup.1H-NMR (CDCl3): 1.71 (2H, quint), 2.45 (2H, t), 2.66
(3H, s), 3.31 (2H, q), 5.56 (1H, br s), 7.06 (2H, d), 7.15-7.29
(3H, m), 7.34-7.51 (5H, m), 7.77 (1H, d), 7.92 (1H, s), 8.51-8.53
(2H, m)
EXAMPLE 14
[0250] Synthesis of
4-(3-chlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(pyri-
dine-3-yl)-5-pyrimidinecarboxamide:
[0251] The title compound was obtained by using 120 mg (0.351 mmol)
of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenylpropyl) acrylamide, 83.0
mg (0.525 mmol) of 3-amidinopyridinium hydrochloride and 34.5 mg
(0.421 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0252] Yield: 85.3 mg (0.193 mmol) (54%)
[0253] MS (ESI, m/z) 443 (M+H).sup.+
[0254] .sup.1H-NMR (CDCl3): 1.81 (2H, quint), 2.52 (2H, t), 2.70
(3H, s), 3.40 (2H, q), 7.09-7.47 (8H, m), 7.76-7.70 (3H, m), 8.40
(1H, d), 8.59 (1H, d), 9.12 (1H, s)
EXAMPLE 15
[0255] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-N-(3-phenylpropyl)-5-p-
yrimidinecarboxamide:
[0256] The title compound was obtained by using 120 mg (0.351 mmol)
of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenylpropyl) acrylamide, 50.0
mg (0.531 mmol) of acetamidine hydrochloride and 34.5 mg (0.421
mmol) of sodium acetate, in the same manner as that of Example
1.
[0257] Yield: 28.6 mg (0.0753 mmol) (22%)
[0258] MS (ESI, m/z) 380 (M+H).sup.+
[0259] .sup.1H-NMR (CDCl3): 1.68 (2H, quint), 2.43 (2H, t), 2.58
(3H, s), 2.75 (3H, s), 3.29 (2H, q), 5.45 (1H, br t), 7.05 (2H, d),
7.15-7.43 (5H, m), 7.79 (1H, m)
EXAMPLE 16
[0260] Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenyl-
propyl)-5-pyrimidinecarboxamide:
[0261] The title compound was obtained by using 120 mg (0.351 mmol)
of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenylpropyl) acrylamide, 146
mg (0.525 mmol) of methylisothiourea-sulfate and 34.5 mg (0.421
mmol) of sodium acetate, in the same manner as that of Example
1.
[0262] Yield: 39.0 mg (0.0947 mmol) (27%)
[0263] MS (ESI, m/z) 317 (M+H).sup.+
[0264] .sup.1H-NMR (CDCl3): 1.68 (2H, quint), 2.43 (2H, t), 2.53
(3H, s), 2.60 (3H,s), 3.27 (2H, q), 5.54 (1H, br s), 7.04 (2H, d),
7.15-7.42 (5H, m), 7.66 (1H, d), 7.79 (1H, s).
EXAMPLE 17
[0265] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-N-(3-phenyl-2-propen-1-
-yl)-5-pyrimidinecarboxamide:
[0266] The title compound was obtained by using 100 mg (0.294 mmol)
of 2-acetyl-3-(3-chlorophenyl)-N-(3-phenyl-2-propen-1-yl)
acrylamide, 41.7 mg (0.441 mmol) of acetamidine hydrochloride and
48.2 mg (0.588 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0267] Yield: 45.5 mg (0.120 mmol) (41%)
[0268] MS (ESI, m/z) 378 (M+H).sup.+
[0269] .sup.1H-NMR (CDCl3): 2.62 (3H, s), 2.76 (3H, s), 4.04 (2H,
td), 5.56 (1H, br t), 5.88 (1H, dt), 6.30 (1H, d), 7.22-7.39 (7H,
m), 7.64 (1H, dt), 7.81 (1H, t).
EXAMPLE 18
[0270] Synthesis of
4-(3,4-dichlorophenyl)-2,6-dimethyl-N-(3-phenylpropyl)-
-5-pyrimidinecarboxamide:
[0271] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
37.7 mg (0.399 mmol) of acetamidine hydrochloride and 43.6 mg
(0.532 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0272] Yield: 91.5 mg (0.221 mmol) (83%)
[0273] MS (ESI, m/z) 414 (M+H).sup.+
[0274] .sup.1H-NMR (CDCl3): 1.72 (2H, quint), 2.48 (2H, t), 2.56
(3H, s), 2.74 (3H, s), 3.31 (2H, q), 5.55 (1H, br t), 7.05 (2H, d),
7.15-7.21 (1H, m), 7.24-7.29 (2H, m), 7.49 (1H, d), 7.62-7.65 (1H,
m), 7.93 (1H, d).
EXAMPLE 19
[0275] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
pyridine-3-yl)-5-pyrimidinecarboxamide:
[0276] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
62.5 mg (0.399 mmol) of benzamidine hydrochloride and 43.6 mg
(0.532 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0277] Yield: 65.3 mg (0.137 mmol) (51%)
[0278] MS (ESI, m/z) 477 (M+H).sup.+
[0279] .sup.1H-NMR (CDCl3): 1.83 (2H, quint), 2.56 (2H, t), 2.71
(3H, s), 3.42 (2H, q), 7.10 (2H, d), 7.16-7.31 (3H, m), 7.36-7.40
(1H, m), 7.53 (1H, d), 7.76 (1H, dd), 7.96 (1H, d), 8.48 (1H, br),
8.62 (1H, m), 9.24 (1H, br s).
EXAMPLE 20
[0280] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-phenyl-N-(3-phenylpr-
opyl)-5-pyrimidinecarboxamide:
[0281] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
62.5 mg (0.399 mmol) of benzamidine hydrochloride and 43.6 mg
(0.532 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0282] Yield: 129 mg (0.271 mmol) (100%)
[0283] MS (ESI, m/z) 476 (M+H).sup.+
[0284] .sup.1H-NMR (CDCl3): 1.78 (2H, quint), 2.51 (2H, t), 2.68
(3H, s), 3.37 (2H, q), 5.52 (1H, br t), 7.09 (2H, d), 7.19-7.30
(3H, m), 7.45 (1H, t), 7.49-7.57 (3H, m), 7.81 (2H, d), 8.52 (2H,
m).
EXAMPLE 21
[0285] Synthesis of
4-(3,5-dichlorophenyl-6-methyl-N-(3-phenylpropyl)-2-(p-
yridine-3-yl)-5-pyrimidinecarboxamide:
[0286] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
62.9 mg (0.399 mmol) of 3-amidinopyridinium hydrochloride and 43.6
mg (0.532 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0287] Yield: 145 mg (0.304 mmol) (111%)
[0288] MS (ESI, m/z) 477 (M+H).sup.+
[0289] .sup.1H-NMR (CDCl3): 1.86 (2H, quint), 2.56 (2H, t), 2.64
(3H, s), 3.44 (2H, q), 7.12-7.37 (6H, m), 7.43-7.44 (1H, m), 7.68
(2H, d), 8.09 (1H, br), 8.37 (1H, br), 8.52-8.56 (1H, m), 9.01 (1H,
s).
EXAMPLE 22
[0290] Synthesis of
4-(3,5-dichlorophenyl)-2,6-dimethyl-N-(3-phenylpropyl)-
-5-pyrimidinecarboxamide:
[0291] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
37.7 mg (0.399 mmol) of acetamidine hydrochloride and 43.6 mg
(0.532 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0292] Yield: 51.8 mg (0.125 mmol) (48%)
[0293] MS (ESI, m/z) 414 (M+H).sup.+
[0294] .sup.1H-NMR (CDCl3): 1.74 (2H, quint), 2.48 (2H, t), 2.57
(3H, s), 2.75 (3H, s), 33.2 (2H, q), 5.54 (1H, br t), 7.08 (2H, d),
7.16-7.29 (3H, m), 7.41 (1H, m), 7.68 (2H, d).
EXAMPLE 23
[0295] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-2-phenyl-N-(4-phenylbu-
tyl)-5-pyrimidinecarboxamide:
[0296] The title compound was obtained by using 100 mg (0.256 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(4-phenylbutyl) acrylamide,
60.1 mg (0.384 mmol) of benzamidine hydrochloride and 42.0 mg
(0.512 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0297] Yield: 104 mg (0.212 mmol) (80%)
[0298] MS (ESI, m/z) 490 (M+H).sup.+
[0299] .sup.1H-NMR (CDCl3): 1.38-1.54 (4H, br), 2.57 (2H, t), 2.64
(3H, s), 3.32 (2H, q), 5.60 (1H, br t), 7.10-7.30 (5H, m),
7.48-7.52 (4H, m), 7.73-7.76 (1H, m), 8.04-8.05 (1H, m), 8.49-8.52
(2H, m).
EXAMPLE 24
[0300] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-N-(4-phenylbutyl)-2-(p-
yridine-3-yl)-5-pyrimidinecarboxamide:
[0301] The title compound was obtained by using 100 mg (0.256 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(4-phenylbutyl) acrylamide,
60.5 mg (0.384 mmol) of 3-amidinopyridinium hydrochloride and 42.0
mg (0.512 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0302] Yield: 83.6 mg (0.170 mmol) (65%)
[0303] MS (ESI, m/z) 491 (M+H).sup.+
[0304] .sup.1H-NMR (CDCl3): 1.49-1.58 (4H, br), 2.56-2.64 (2H, br),
2.68 (3H, s), 3.36-3.44 (2H, br), 7.11-7.20 (3H, m), 7.25-7.36 (3H,
m), 7.50-7.52 (2H, m), 7.71-7.75 (1H, m), 7.92 (1H, d), 8.32-8.34
(1H, m), 8.56-8.60 (1H, m), 9.12 (1H, m).
EXAMPLE 25
[0305] Synthesis of
4-(3,4-dichlorophenyl)-2,6-dimethyl-N-(4-phenylbutyl)--
5-pyrimidinecarboxamide:
[0306] The title compound was obtained by using 100 mg (0.256 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(4-phenylbutyl) acrylamide,
36.3 mg (0.384 mmol) of acetamidine hydrochloride and 42.0 mg
(0.512 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0307] Yield: 53.3 mg (0.124 mmol) (46%)
[0308] MS (ESI, m/z) 428 (M+H).sup.+
[0309] .sup.1H-NMR (CDCl3): 1.36-1.44 (4H, m), 2.53-2.58 (5H, m),
2.74 (3H, s), 3.29 (2H, q), 5.48 (1H, br t), 7.09-7.20 (3H, m),
7.24-7.29 (2H, m), 7.48 (1H, d), 7.62-7.65 (1H, m), 7.93 (1H,
d).
EXAMPLE 26
[0310] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(4-ph-
enylbutyl)-5-pyrimidinecarboxamide:
[0311] The title compound was obtained by using 100 mg (0.256 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(4-phenylbutyl) acrylamide,
53.5 mg (0.192 mmol) of methylisothiourea-sulfate and 42.0 mg
(0.512 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0312] Yield: 57.2 mg (0.124 mmol) (46%)
[0313] MS (ESI, m/z) 460 (M+H).sup.+
[0314] .sup.1H-NMR (CDCl3): 1.34-1.52 (4H, br), 2.52-2.60 (8H, m),
3.28 (2H, q), 5.48 (1H, br t), 7.09-7.12 (2H, m), 7.15-7.20 (1H,
m), 7.24-7.29 (2H, m), 7.47 (1H, d), 7.63-7.67 (1H, m), 7.93 (1H,
d).
EXAMPLE 27
[0315] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-2-phenyl-N-(2-phenylet-
hyl)-5-pyrimidinecarboxamide:
[0316] The title compound was obtained by using 100 mg (0.276 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(2-phenylethyl) acrylamide,
64.8 mg (0.414 mmol) of benzamidine hydrochloride and 45.3 mg
(0.552 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0317] Yield: 54.6 mg (0.118 mmol) (43%)
[0318] MS (ESI, m/z) 462 (M+H).sup.+
[0319] .sup.1H-NMR (CDCl3): 2.61 (3H, s), 2.74 (2H, t), 3.63 (2H,
q), 5.51 (1H, br t), 6.91-6.94 (2H, m), 7.18-7.25 (3H, m),
7.47-7.55 (4H, m), 7.73 (1H, dd), 8.03 (1H, d), 8.48-8.51 (2H,
m).
EXAMPLE 28
[0320] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-N-(2-phenylethyl)-2-(p-
yridine-3-yl)-5-pyrimidinecarboxamide:
[0321] The title compound was obtained by using 100 mg (0.276 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(2-phenylethyl) acrylamide,
65.2 mg (0.414 mmol) of 3-amidinopyridinium hydrochloride and 45.3
mg (0.552 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0322] Yield: 114 mg (0.246 mmol) (89%)
[0323] MS (ESI, m/z) 463 (M+H).sup.+
[0324] .sup.1H-NMR (CDCl3): 2.62 (3H, s), 2.82 (2H, t), 3.70 (2H,
q), 6.99-7.02 (2H, m), 7.17-7.40 (5H, m), 7.53 (1H, d), 7.72 (1H,
dd), 7.90 (1H, d), 8.11-8.17 (1H, br), 8.53-8.56 (1H, m), 9.12 (1H,
s).
EXAMPLE 29
[0325] Synthesis of
4-(3,4-dichlorophenyl)-2,6-dimethyl-N-(2-phenylethyl)--
5-pyrimidinecarboxamide:
[0326] The title compound was obtained by using 100 mg (0.276 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(2-phenylethyl) acrylamide,
39.1 mg (0.414 mmol) of acetamidine hydrochloride and 45.3 mg
(0.552 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0327] Yield: 43.2 mg (0.108 mmol) (89%)
[0328] MS (ESI, m/z) 400 (M+H).sup.+
[0329] .sup.1H-NMR (CDCl3): 2.50 (3H, s), 2.68-2.72 (5H, m), 3.59
(2H, q), 5.47 (1H, br s), 6.89-6.91 (2H, m), 7.17-7.26 (3H, m),
7.50 (1H, d), 7.59-7.63 (1H, m), 7.89 (1H, d).
EXAMPLE 30
[0330] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(2-ph-
enylethyl)-5-pyrimidinecarboxamide:
[0331] The title compound was obtained by using 100 mg (0.276 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-(2-phenylethyl) acrylamide,
57.6 mg (0.207 mmol) of methylisothiourea-sulfate and 45.3 mg
(0.552 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0332] Yield: 50.3 mg (0.116 mmol) (43%)
[0333] MS (ESI, m/z) 432 (M+H).sup.+
[0334] .sup.1H-NMR (CDCl3): 2.46 (3H, s), 2.58 (3H, s), 2.70 (2H,
t), 3.58 (2H, q), 5.46 (1H, br t), 6.89-6.92 (2H, m), 7.18-7.26
(3H, m), 7.49 (1H, d), 7.60-7.64 (1H, m), 7.90 (1H, d).
EXAMPLE 31
[0335] Synthesis of
4-(3,4-dichlorophenyl)-2,6-dimethyl-N-(3,3-diphenylpro-
pyl)-5-pyrimidinecarboxamide:
[0336] 120 mg (0.265 mmol) of
2-acetyl-3-(3,4-dichlorophenyl)-N-(3,3-diphe- nylpropyl) acrylamide
was dissolved in 5 ml of DMF. 37.6 mg (0.398 mmol) of acetamidine
hydrochloride and 26.1 mg of (0.318 mmol) of sodium acetate were
added thereto and stirred at 100.degree. C. overnight. After the
solvent was evaporated under reduced pressure, the reaction mixture
was diluted with ethyl acetate and washed with saturated aqueous
sodium chloride solution. The organic layer was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The obtained residue was dissolved in 10 ml of toluene.
120 mg (0.530 mmol) of DDQ
(2,3-dichloro-5,6-dicyano-1,4-benzoquinone; hereinafter abbreviated
as DDQ) was added thereto and stirred at 100.degree. C. overnight.
After filtration of insoluble matters and evaporation of the
solvent under reduced pressure, the filtrate was diluted with ethyl
acetate and washed with saturated aqueous sodium chloride solution.
The organic layer was dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1)
to obtain the title compound.
[0337] Yield: 20.0 mg (0.0408 mmol) (15%)
[0338] MS (ESI, m/z) 490 (M+H).sup.+
[0339] .sup.1H-NMR (CDCl3): 2.12 (2H, q), 2.55 (3H, s), 2.75 (3H,
s), 3.25 (2H, q), 3.75 (1H, t), 5.43 (1H, br t), 7.11-7.29 (10H,
m), 7.47 (1H, d), 7.60-7.64 (1H, m), 7.93 (1H, d).
EXAMPLE 32
[0340] Synthesis of
4-(3,5-dichlorophenyl)-2,6-dimethyl-N-(3,3-diphenylpro-
pyl)-5-pyrimidinecarboxamide:
[0341] 111 mg (0.246 mmol) of
2-acetyl-3-(3,5-dichlorophenyl)-N-(3,3-diphe- nylpropyl) acrylamide
was dissolved in 5 ml of DMF. 34.9 mg (0.369 mmol) of acetamidine
hydrochloride and 24.2 mg of (0.295 mmol) of sodium acetate were
added thereto and stirred at 100.degree. C. overnight. After the
solvent was evaporated under reduced pressure, the reaction mixture
was diluted with ethyl acetate and washed with saturated aqueous
sodium chloride solution. The organic layer was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The obtained residue was dissolved in 10 ml of toluene.
112 mg (0.492 mmol) of DDQ was added thereto and stirred at
100.degree. C. overnight. After filtration of insoluble matters and
evaporation of the solvent under reduced pressure, the filtrate was
diluted with ethyl acetate and washed with saturated aqueous sodium
chloride solution. The organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 1/1) to obtain the title compound.
[0342] Yield: 30.2 mg (0.0616 mmol) (25%)
[0343] MS (ESI, m/z) 490 (M+H).sup.+
[0344] .sup.1H-NMR (CDCl3): 2.14 (2H, q), 2.55 (3H, s), 2.75 (3H,
s), 3.27 (2H, q), 3.69 (1H, t), 5.41 (1H, br t), 7.13-7.19 (5H, m),
7.24-7.29 (5H, m), 7.34 (1H, d), 7.67 (2H, d).
EXAMPLE 33
[0345] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-5-p-
yrimidinecarboxamide:
[0346] 100 mg (0.224 mmol) of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylthi-
o)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml
of dichloromethane. 77.3 mg (0.448 mmol) of mCPBA
(m-chloroperbenzoic acid; hereinafter abbreviated as mCPBA) was
added thereto at 0.degree. C. and stirred at the same temperature
for 6 hours. 1 ml of saturated aqueous sodium sulfite solution was
added thereto at the same temperature and stirred for 30 minutes
heating to room temperature. After the reaction mixture was diluted
with dichloromethane, the organic layer was washed with saturated
aqueous sodium chloride solution and dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The obtained
residue was dissolved in 5 ml of ethanol and 16.9 mg (0.448 mmol)
of sodium borohydride was added at room temperature and stirred for
1 hour. 5 ml of 1N hydrochloric acid was added at the same
temperature, stirred at room temperature for 30 minutes and then
concentrated under reduced pressure. After the obtained residue was
diluted with dichloromethane, the organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=3/1) to obtain the title compound.
[0347] Yield: 50.8 mg (0.127 mmol) (57%)
[0348] MS (ESI, m/z) 400 (M+H).sup.+
[0349] .sup.1H-NMR (CDCl3): 1.75 (2H, quint), 2.49 (2H, t), 2.62
(3H, s), 3.34 (2H, q), 5.59 (1H, br t), 7.06 (2H, d), 7.15-7.20
(1H, m), 7.24-7.29 (2H, m), 7.52 (1H, d), 7.67 (1H, dd), 7.96 (1H,
d).
EXAMPLE 34
[0350] Synthesis of
4-(3,4-dichlorophenyl)-2,6-dimethyl-N-[2-(pyridine-3-y- l)
ethyl]-5-pyrimidinecarboxamide:
[0351] The title compound was obtained by using 140 mg (0.385 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-[2-(pyridine-3-yl) ethyl]
acrylamide, 55.3 mg (0.585 mmol) of acetamidine hydrochloride and
64.0 mg (0.780 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0352] Yield: 37.7 mg (0.0939 mmol) (24%)
[0353] MS (ESI, m/z) 401 (M+H).sup.+
[0354] .sup.1H-NMR (CDCl3): 2.52 (3H, s), 2.72-2.76 (5H, m), 3.59
(2H, q), 5.55 (1H, br t), 7.16-7.20 (1H, m), 7.27-7.31 (1H, m),
7.51 (1H, d), 7.61-7.65 (1H, m), 7.91 (1H, d), 8.28 (1H,s),
8.44-8.45 (1H, m).
EXAMPLE 35
[0355] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-[2-(p-
yridine-3-yl) ethyl]-5-pyrimidinecarboxamide:
[0356] The title compound was obtained by using 140 mg (0.385 mmol)
of 2-acetyl-3-(3,4-dichlorophenyl)-N-[2-(pyridine-3-yl) ethyl]
acrylamide, 81.4 mg (0.292 mmol) of methylisothiourea-sulfate and
64.0 mg (0.780 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0357] Yield: 45.0 mg (0.104 mmol) (27%)
[0358] MS (ESI, m/z) 433 (M+H).sup.+
[0359] .sup.1H-NMR (CDCl3): 2.44 (3H, s), 2.56 (3H, s), 2.73 (2H,
t), 3.57 (2H, q), 6.13 (1H, br s), 7.13-7.17 (1H, m), 7,28-7.32
(1H, m), 7.48 (1H, d), 7.60-7.63 (1H, m), 7.86-7.87 (1H, m), 8.16
(1H, s), 8.33 (1H, d).
EXAMPLE 36
[0360] Synthesis of
4-(4-methoxyphenyl)-6-methyl-2-phenyl-N-(3-phenylpropy-
l)-5-pyrimidinecarboxamide:
[0361] The title compound was obtained by using 131 mg (0.388 mmol)
of 2-acetyl-3-(4-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 91.1
mg (0.582 mmol) of benzamidine hydrochloride and 80.0 mg (0.975
mmol) of sodium acetate, in the same manner as that of Example
1.
[0362] Yield: 53.5 mg (0.122 mmol) (31%)
[0363] MS (ESI, m/z) 438 (M+H).sup.+
[0364] .sup.1H-NMR (CDCl3): 1.71 (2H, quint), 2.45 (2H, t), 2.64
(3H, s), 3.32 (2H, q), 3.79 (3H, s), 5.58 (1H, br t), 6.96 (2H, d),
7.05 (2H, d), 7.17-7.28 (3H, m), 7.47-7.50 (3H, m), 7.90 (2H, d),
8.51-8.54 (2H, m).
EXAMPLE 37
[0365] Synthesis of
4-(4-methoxyphenyl)-6-methyl-N-(3-phenylpropyl)-2-(pyr-
idine-3-yl)-5-pyrimidinecarboxamide:
[0366] The title compound was obtained by using 137 mg (0.406 mmol)
of 2-acetyl-3-(4-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 96.0
mg (0.609 mmol) of 3-amidinopyridinium hydrochloride and 80.0 mg
(0.975 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0367] Yield: 23.0 mg (0.0524 mmol) (13%)
[0368] MS (ESI, m/z) 439 (M+H).sup.+
[0369] .sup.1H-NMR (CDCl3): 1.79 (2H, quint), 2.51 (2H, t), 2.67
(3H, s), 3.40 (2H, q), 3.81 (3H, s), 6.96-7.36 (8H, m), 7.90 (2H,
dt), 8.46 (1H, dd), 8.62 (1H, dt), 9.28 (1H, d).
EXAMPLE 38
[0370] Synthesis of
4-methyl-N-(3-phenylpropyl)-2,6-di(pyridine-3-yl)-5-py-
rimidinecarboxamide:
[0371] The title compound was obtained by using 177 mg (0.546 mmol)
of 2-acetyl-N-(3-phenylpropyl)-3-(pyridine-3-yl) acrylamide, 129 mg
(0.819 mmol) of 3-amidinopyridinium hydrochloride and 89.4 mg (1.09
mmol) of sodium acetate, in the same manner as that of Example
1.
[0372] Yield: 138 mg (0.337 mmol) (62%)
[0373] MS (ESI, m/z) 410 (M+H).sup.+
[0374] .sup.1H-NMR (CDCl3): 1.81 (2H, quint), 2.53 (2H, t), 2.71
(3H, s), 3.45 (3H, s), 3.41 (2H, q), 7.08-7.11 (2H, m), 7.14-7.20
(1H, m), 7.23-7.28 (2H, m), 7.32-7.39 (2H, m), 7.98 (1H, br t),
8.20 (1H, dt), 8.39 (1H, dd), 8.56 (1H, dt), 8.68 (1H, dd),
9.00-9.01 (1H, m), 9.11-9.12 (1H, m).
EXAMPLE 39
[0375] Synthesis of
2,4-dimethyl-N-(3-phenylpropyl)-6-(pyridine-3-yl)-5-py-
rimidinecarboxamide:
[0376] The title compound was obtained by using 177 mg (0.546 mmol)
of 2-acetyl-N-(3-phenylpropyl)-3-(pyridine-3-yl) acrylamide, 77.0
mg (0.814 mmol) of acetamidine hydrochloride and 89.4 mg (1.09
mmol) of sodium acetate, in the same manner as that of Example
1.
[0377] Yield: 82.3 mg (0.238 mmol) (44%)
[0378] MS (ESI, m/z) 347 (M+H).sup.+
[0379] .sup.1H-NMR (CDCl3): 1.70 (2H, quint), 2.45 (2H, t), 2.56
(3H, s), 2,71 (3H, s), 3.29 (2H, q), 6.34 (1H, br t), 7.05 (2H, d),
8.06 (1H, dt), 8.51 (1H, dd), 8.77-8.78 (1H, m).
EXAMPLE 40
[0380] Synthesis of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(-
3-phenylpropyl)-5-pyrimidinecarboxamide:
[0381] 214 mg (0.479 mmol) of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylthi-
o)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide synthesized in
Example 7 was dissolved in 10 ml of dichloromethane. 165 mg (0.958
mmol) of mCPBA (m-chloroperbenzoic acid) was added thereto at
0.degree. C. and stirred at the same temperature for 6 hours. 5 ml
of saturated aqueous sodium bisulfite solution was added thereto at
the same temperature and stirred for 30 minutes heating to room
temperature. After the reaction mixture was diluted with
dichloromethane, the organic layer was washed with saturated
aqueous sodium chloride solution and dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by the silica gel chromatography (hexane/ethyl
acetate=5/1) to obtain the title compound.
[0382] MS (ESI, m/z) 478 (M+H).sup.+ 476 (M-H).sup.-
[0383] .sup.1H-NMR (CDCl3): 1.79 (2H, quint), 2.52 (2H, t), 2.72
(3H, s), 3.28 (3H, s), 3.36 (2H, q), 6.34 (1H, br t), 7.07-7.10
(2H, m), 7.16-7.21 (1H, m), 7.25-7.30 (2H, m), 7.52 (1H, d), 7.74
(1H, dd), 8.03 (1H, d).
EXAMPLE 41
[0384] Synthesis of
4-methyl-2-phenyl-N-(3-phenylpropyl)-6-(pyridine-3-yl)-
-5-pyrimidinecarboxamide:
[0385] The title compound was obtained by using 177 mg (0.546 mmol)
of 2-acetyl-N-(3-phenylpropyl)-3-(pyridine-3-yl) acrylamide, 128 mg
(0.819 mmol) of benzamidine hydrochloride and 89.4 mg (1.09 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0386] Yield: 116 mg (0.284 mmol) (51%)
[0387] MS (ESI, m/z) 409 (M+H).sup.+
[0388] .sup.1H-NMR (CDCl3): 1.75 (2H, quint), 2.50 (2H, t), 2.67
(3H, s), 3.34 (2H, q), 5.87 (1H, br t), 7.06-7.09 (2H, m),
7.15-7.38 (4H, m), 7.47-7.53 (3H, m), 8.18-8.22 (1H, m), 8.48-8.52
(2H, m), 8.65 (1H, dd), 9.06 (1H, d).
EXAMPLE 42
[0389] Synthesis of
4-methyl-2-(methylthio)-N-(3-phenylpropyl)-6-(pyridine-
-3-yl)-5-pyrimidinecarboxamide:
[0390] The title compound was obtained by using 177 mg (0.546 mmol)
of 2-acetyl-N-(3-phenylpropyl)-3-(pyridine-3-yl) acrylamide, 114 mg
(0.410 mmol) of methylisothiourea-sulfate and 89.4 mg (1.09 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0391] Yield: 56.9 mg (0.150 mmol) (27%)
[0392] MS (ESI, m/z) 379 (M+H).sup.+
[0393] .sup.1H-NMR (CDCl3): 1.71 (2H, quint), 2.47 (2H, t), 2.55
(3H, s), 2.60 (3H, s), 3.30 (2H, q), 5.64 (1H, br t), 7.04-7.07
(2H, m), 7.17-7.36 (4H, m), 8.11 (1H, dt), 8.65 (1H, dd), 9.00 (1H,
d).
EXAMPLE 43
[0394] Synthesis of
2-amino-4-(3,4-dichlorophenyl)-6-methyl-N-(3-phenylpro-
pyl)-5-pyrimidinecarboxamide:
[0395] 114 mg (0.238 mmol) of
4-(3-chlorophenyl)-6-methyl-2-methylsulfonyl-
-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 10 ml
of THF. 5 ml of 28% aqueous ammonia was added at 0.degree. C. and
stirred at room temperature for 12 hours. After the reaction
mixture was diluted with ethyl acetate, the organic layer was
washed with saturated aqueous sodium chloride solution and dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by the silica gel
chromatography (dichloromethane/methanol=100/1 to 10/1) to obtain
the title compound.
[0396] MS (ESI, m/z) 452 (M+H).sup.+
[0397] .sup.1H-NMR (CDCl3): 1.69 (2H, quint), 2.42-2.48 (4H, m),
3.26 (2H, q), 5.25 (2H, br s), 5.45 (1H, br t), 7.04-7.07 (2H, m),
7,07-7.20 (1H, m), 7.23-7.29 (2H, m), 7.46 (1H, d), 7.57 (1H, dd),
7.86 (1H, d).
EXAMPLE 44
[0398] Synthesis of
4-(4-methoxyphenyl)-6-methyl-2-(methylthio)-N-(3-pheny-
lpropyl)-5-pyrimidinecarboxamide:
[0399] The title compound was obtained by using 215 mg (0.663 mmol)
of 2-acetyl-3-(4-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 138
mg (0.995 mmol) of methylisothiourea-sulfate and 109 mg (1.33 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0400] Yield: 38.5 mg (0.0945 mmol) (15%)
[0401] MS (ESI, m/z) 408 (M+H).sup.+
[0402] .sup.1H-NMR (CDCl3): 1.69 (2H, quint), 2.43 (2H, t), 2.52
(3H, s), 2.60 (3H, s), 3.29 (2H, q), 3.77 (3H, s), 5.49 (1H, br t),
6.91-6.96 (2H, m), 7.03-7.06 (2H, m), 7.14-7.28 (3H, m), 7.78-7.81
(2H, m).
EXAMPLE 45
[0403] Synthesis of
4-methyl-6-(3-nitrophenyl)-2-phenyl-N-(3-phenylpropyl)-
-5-pyrimidinecarboxamide:
[0404] The title compound was obtained by using 100 mg (0.284 mmol)
of .sup.2-acetyl-3-(3-nitrophenyl)-N-(3-phenylpropyl) acrylamide,
66.7 mg (0.426 mmol) of benzamidine hydrochloride and 46.6 mg
(0.568 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0405] Yield: 86.0 mg (0.190 mmol) (68%)
[0406] MS (ESI, m/z) 453 (M+H).sup.+
[0407] .sup.1H-NMR (CDCl3): 1.74 (2H, quint), 2.49 (2H, t), 2.66
(3H, s), 3.33 (2H, q), 5.81 (1H, br t), 7.05 (2H, d), 7.17-7.28
(3H, m), 7.47-7.62 (4H, m), 8.20-8.29 (2H, m), 8.49-8.52 (2H, m),
8.77-8.78 (1H, m).
EXAMPLE 46
[0408] Synthesis of
4-methyl-6-(3-nitrophenyl)-N-(3-phenylpropyl)-2-(pyrid-
ine-3-yl)-5-pyrimidinecarboxamide:
[0409] The title compound was obtained by using 100 mg (0.284 mmol)
of 2-acetyl-3-(3-nitrophenyl)-N-(3-phenylpropyl) acrylamide, 67.1
mg (0.426 mmol) of 3-amidinopyridinium hydrochloride and 46.6 mg
(0.568 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0410] Yield: 74.9 mg (0.165 mmol) (61%)
[0411] MS (ESI, m/z) 454 (M+H).sup.+
[0412] .sup.1H-NMR (CDCl3): 1.82 (2H, quint), 2.55 (2H, t), 2.74,
(3H, s), 3.43 (2H, q), 7.07-7.10 (2H, m), 7.16-7.29 (4H, m), 7.62
(1H, t), 7.89 (1H, br t), 8.23-8.40 (3H, m), 8.59-8.63 (2H, m),
9.12 (1H, d).
EXAMPLE 47
[0413] Synthesis of
2,4-dimethyl-6-(3-nitrophenyl)-N-(3-phenylpropyl)-5-py-
rimidinecarboxamide:
[0414] The title compound was obtained by using 100 mg (0.284 mmol)
of 2-acetyl-3-(3-nitrophenyl)-N-(3-phenylpropyl) acrylamide, 40.3
mg (0.426 mmol) of acetamidine hydrochloride and 46.6 mg (0.568
mmol) of sodium acetate, in the same manner as that of Example
1.
[0415] Yield: 31.3 mg (0.0802 mmol) (28%)
[0416] MS (ESI, m/z) 391 (M+H).sup.+
[0417] .sup.1H-NMR (CDCl3): 1.71 (2H, quint), 2.47 (2H, t), 2.59
(3H, s), 2.77 (3H, s), 3.31 (2H, q), 5.64 (1H, br t), 7.02-7.05
(2H, m), 7.14-7.27 (3H, m), 7.59 (1H, t), 8.11-8.15 (1H, m),
8.25-8.29 (1H, m), 8.68-8.69 (1H, m).
EXAMPLE 48
[0418] Synthesis of
4-methyl-2-(methylthio)-6-(3-nitrophenyl)-N-(3-phenylp-
ropyl)-5-pyrimidinecarboxamide:
[0419] The title compound was obtained by using 100 mg (0.284 mmol)
of 2-acetyl-3-(3-nitrophenyl)-N-(3-phenylpropyl) acrylamide, 59.3
mg (0.213 mmol) of methylisothiourea-sulfate and 46.6 mg (0.568
mmol) of sodium acetate, in the same manner as that of Example
1.
[0420] Yield: 20.0 mg (0.0473 mmol) (17%)
[0421] MS (ESI, m/z) 423 (M+H).sup.+
[0422] .sup.1H-NMR (CDCl3): 1.71 (2H, quint), 2.47 (2H, t), 2.56
(3H, s), 2.61 (3H, s), 3.31 (2H, q), 5.59 (1H, br t), 7.04 (2H, d),
7.15-7.28 (3H, m), 7.59 (1H, t), 8.13-8.16 (1H, m), 8.26-8.30 (1H,
m), 8.69-8.70 (1H, m).
EXAMPLE 49
[0423] Synthesis of
4-methyl-6-(3-methylphenyl)-2-phenyl-N-(3-phenylpropyl-
)-5-pyrimidinecarboxamide:
[0424] The title compound was obtained by using 175 mg (0.544 mmol)
of 2-acetyl-3-(3-methylphenyl)-N-(3-phenylpropyl) acrylamide, 127
mg (0.816 mmol) of benzamidine hydrochloride and 88.6 mg (1.08
mmol) of sodium acetate, in the same manner as that of Example
1.
[0425] Yield: 11.0 mg (0.0261 mmol) (4.8%)
[0426] MS (ESI, m/z) 422 (M+H).sup.+
[0427] .sup.1H-NMR (CDCl3): 1.66 (2H, quint), 2.39 (3H, s), 2.40
(2H, t), 2.68 (3H, s), 3.29 (2H, q), 5.43 (1H, br t), 7.04 (2H, d),
7.05-7.28 (4H, m), 7.36 (1H, t), 7.48-7.52 (3H, m), 7.67-7.70 (2H,
m), 8.52-8.55 (2H, m).
EXAMPLE 50
[0428] Synthesis of
4-methyl-6-(3-methylphenyl)-N-(3-phenylpropyl)-2-(pyri-
dine-3-yl)-5-pyrimidinecarboxamide:
[0429] The title compound was obtained by using 175 mg (0.544 mmol)
of 2-acetyl-3-(3-methylphenyl)-N-(3-phenylpropyl) acrylamide, 128
mg (0.816 mmol) of 3-amidinopyridinium hydrochloride and 88.6 mg
(1.08 mmol of sodium acetate in the same manner as that of Example
1.
[0430] Yield: 33.2 mg (0.0786 mmol) (14%)
[0431] MS (ESI, m/z) 423 (M+H).sup.+
[0432] .sup.1H-NMR (CDCl3): 1.72 (2H, quint), 2.40 (3H, s), 2.44
(2H, t), 2.70 (3H, s), 3.34 (2H, q), 6.61 (1H, br t), 7.04-7.07
(2H, m), 7.15-7.39 (5H, m), 7.66-7.69 (2H, m), 8.54 (1H, dd), 8.69
(1H, dt), 9.43 (1H, d).
EXAMPLE 51
[0433] Synthesis of
2,4-dimethyl-6-(3-methylphenyl)-N-(3-phenylpropyl)-5-p-
yrimidinecarboxamide:
[0434] The title compound was obtained by using 175 mg (0.544 mmol)
of 2-acetyl-3-(3-methylphenyl)-N-(3-phenylpropyl) acrylamide, 76.6
mg (0.816 mmol) of acetamidine hydrochloride and 88.6 mg (1.08
mmol) of sodium acetate, in the same manner as that of Example
1.
[0435] Yield: 14.8 mg (0.0412 mmol) (7.8%)
[0436] MS (ESI, m/z) 360 (M+H).sup.+
[0437] .sup.1H-NMR (CDCl3): 1.62 (2H, quint), 2.36 (3H, s), 2.37
(2H, t), 2.58 (3H, s), 2.76 (3H, s), 3.25 (2H, q), 5.36 (1H, br t),
7.02 (2H, d), 7.14-7.34 (5H, m), 7.52-7.55 (2H, m).
EXAMPLE 52
[0438] Synthesis of
4-methyl-6-(3-methylphenyl)-2-(methylthio)-N-(3-phenyl-
propyl)-5-pyrimidinecarboxamide:
[0439] The title compound was obtained by using 175 mg (0.544 mmol)
of 2-acetyl-3-(3-methylphenyl)-N-(3-phenylpropyl) acrylamide, 113
mg (0.406 mmol) of methylisothiourea-sulfate and 88.6 mg (1.08
mmol) of sodium acetate, in the same manner as that of Example
1.
[0440] Yield: 47.7 mg (0.122 mmol) (22%)
[0441] MS (ESI, m/z) 392 (M+H).sup.+
[0442] .sup.1H-NMR (CDCl3): 1.62 (2H, quint), 2.35 (31H, s), 2.37
(2H, t), 2.54 (3H, s), 2.60 (3H, s), 3.24 (2H, q), 5.39 (1H, br t),
7.02 (2H, d), 7.03-7.34 (5H, m), 7.56-7.58 (2H, m).
EXAMPLE 53
[0443] Synthesis of
4-(3-fluorophenyl)-6-methyl-2-phenyl-N-(3-phenylpropyl-
)-5-pyrimidinecarboxamide:
[0444] The title compound was obtained by using 135 mg (0.415 mmol)
of 2-acetyl-3-(3-fluorophenyl)-N-(3-phenylpropyl) acrylamide, 97.1
mg (0.623 mmol) of benzamidine hydrochloride and 67.3 mg (0.820
mmol) of sodium acetate, in the same manner as that of Example
1.
[0445] Yield: 113 mg (0.266 mmol) (66%)
[0446] MS (ESI, m/z) 426 (M+H).sup.+
[0447] .sup.1H-NMR (CDCl3): 1.70 (2H, quint), 2.45 (2H, t), 2.64
(3H, s), 3.30 (2H, q), 5.65 (1H, br t), 7.03-7.07 (2H, m),
7.12-7.29 (4H, m), 7.36-7.52 (4H, m), 7.63-7.68 (2H, m), 8.49-8.53
(2H, m).
EXAMPLE 54
[0448] Synthesis of
4-(3-fluorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(pyri-
dine-3-yl)-5-pyrimidinecarboxamide:
[0449] The title compound was obtained by using 135 mg (0.415 mmol)
of 2-acetyl-3-(3-fluorophenyl)-N-(3-phenylpropyl) acrylamide, 97.7
mg (0.623 mmol) of 3-amidinopyridinium hydrochloride and 67.3 mg
(0.820 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0450] Yield: 97.0 mg (0.227 mmol) (56%)
[0451] MS (ESI, m/z) 427 (M+H).sup.+
[0452] .sup.1H-NMR (CDCl3): 1.79 (2H, quint), 2.52 (2H, t), 2.70
(3H, s), 3.40 (2H, q), 7.08-7.46 (9H, m), 7.61-7.71 (2H, m), 8.46
(1H, dd), 8.62 (1H, dt), 9.25 (1H, d).
EXAMPLE 55
[0453] Synthesis of
4-(3-fluorophenyl)-2,6-dimethyl-N-(3-phenylpropyl)-5-p-
yrimidinecarboxamide:
[0454] The title compound was obtained by using 135 mg (0.415 mmol)
of 2-acetyl-3-(3-fluorophenyl)-N-(3-phenylpropyl) acrylamide, 58.6
mg (0.623 mmol) of acetamidine hydrochloride and 67.3 mg (0.820
mmol) of sodium acetate, in the same manner as that of Example
1.
[0455] Yield: 50.0 mg (0.138 mmol) (34%)
[0456] MS (ESI, m/z) 364 (M+H).sup.+
[0457] .sup.1H-NMR (CDCl3): 1.67 (2H, quint), 2.43 (2H, t), 2.58
(3H, s), 2.75 (3H, s), 3.28 (2H, q), 5.46 (1H, br t), 7.03-7.06
(2H, m), 7.09-7.28 (4H, m), 7.35-7.43 (1H, m), 7.49-7.57 (2H,
m).
EXAMPLE 56
[0458] Synthesis of
4-(3-fluorophenyl)-6-methyl-2-(methylthio)-N-(3-phenyl-
propyl)-5-pyrimidinecarboxamide:
[0459] The title compound was obtained by using 135 mg (0.415 mmol)
of 2-acetyl-3-(3-fluorophenyl)-N-(3-phenylpropyl) acrylamide, 86.3
mg (0.310 mmol) of methylisothiourea-sulfate and 67.3 mg (0.820
mmol) of sodium acetate, in the same manner as that of Example
1.
[0460] Yield: 62.0 mg (0.157 mmol) (39%)
[0461] MS (ESI, m/z) 396 (M+H).sup.+
[0462] .sup.1H-NMR (CDCl3): 1.68 (2H, quint), 2.43 (2H, t), 2.52
(3H, s), 2.59 (3H, s), 3.27 (2H, q), 5.59 (1H, br t), 7.03-7.06
(2H, m), 7.10-7.28 (4H, m), 7.34-7.41 (1H, m), 7.51-7.58 (2H,
m).
EXAMPLE 57
[0463] Synthesis of
4-(3-methoxyphenyl)-6-methyl-2-(methylthio)-N-(3-pheny-
lpropyl)-5-pyrimidinecarboxamide:
[0464] The title compound was obtained by using 300 mg (0.889 mmol)
of 2-acetyl-3-(3-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 186
mg (0.668 mmol) of methylisothiourea-sulfate and 146 mg (1.78 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0465] Yield: 194 mg (0.476 mmol) (54%)
[0466] MS (ESI, m/z) 408 (M+H).sup.+
[0467] .sup.1H-NMR (CDCl3): 1.64 (2H, quint), 2.39 (2H, t), 2.53
(3H, s), 2.60 (3H, s), 3.25 (2H, q), 3.78 (3H, s), 5.47 (1H, br t),
6.94-7.05 (3H, m), 7.14-7.37 (6H, m).
EXAMPLE 58
[0468] Synthesis of
4-(3-methoxyphenyl)-6-methyl-2-phenyl-N-(3-phenylpropy-
l)-5-pyrimidinecarboxamide:
[0469] The title compound was obtained by using 200 mg (0.593 mmol)
of 2-acetyl-3-(3-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 139
mg (0.885 mmol) of benzamidine hydrochloride and 96.8 mg (1.18
mmol) of sodium acetate, in the same manner as that of Example
1.
[0470] Yield: 56.0 mg (0.128 mmol) (22%)
[0471] MS (ESI, m/z) 438 (M+H).sup.+
[0472] .sup.1H-NMR (CDCl3): 1.67 (2H, quint), 2.41 (2H, t), 2.66
(3H, s), 3.29 (2H, q), 3.81 (3H, s), 5.65 (1H, br t), 6.97-7.52
(12H, m), 8.51-8.58 (2H, m).
EXAMPLE 59
[0473] Synthesis of
4-(3-methoxyphenyl)-6-methyl-N-(3-phenylpropyl)-2-(pyr-
idine-3-yl)-5-pyrimidinecarboxamide:
[0474] The title compound was obtained by using 200 mg (0.593 mmol)
of 2-acetyl-3-(3-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 140
mg (0.885 mmol) of 3-amidinopyridinium hydrochloride and 96.8 mg
(1.18 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0475] Yield: 39.0 mg (0.0889 mmol) (15%)
[0476] MS (ESI, m/z) 439 (M+H).sup.+
[0477] .sup.1H-NMR (CDCl3): 1.74 (2H, quint), 2.46 (2H, t), 2.70
(3H, s), 3.36 (2H, q), 3.82 (3H, s), 6.70 (1H, br t), 6.99-7.49
(10H, m), 8.55-8.70 (2H, m), 9.42 (1H, br s).
EXAMPLE 60
[0478] Synthesis of
4-(3-methoxyphenyl)-2,6-dimethyl-N-(3-phenylpropyl)-5--
pyrimidinecarboxamide:
[0479] The title compound was obtained by using 300 mg (0.889 mmol)
of 2-acetyl-3-(3-methoxyphenyl)-N-(3-phenylpropyl) acrylamide, 126
mg (1.34 mmol) of acetamidine hydrochloride and 146 mg (1.78 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0480] Yield: 72.0 mg (0.192 mmol) (21%)
[0481] MS (ESI, m/z) 376 (M+H).sup.+
[0482] .sup.1H-NMR (CDCl3): 1.63 (2H, quint), 2.38 (2H, t), 2.57
(3H, s), 2.74 (3H, s), 3.25 (2H, q), 3.78 (3H, s), 5.47 (1H, br t),
6.93-9.97 (2H, m), 7.14-7.36 (7H, m).
EXAMPLE 61
[0483] Synthesis of
2-(t-butyl)-4-(3,5-dichlorophenyl)-6-methyl-N-(3-pheny-
lpropyl)-5-pyrimidinecarboxamide:
[0484] 1) Synthesis of 3-oxo-N-(3-phenylpropyl) butylamide:
[0485] 3.00 g of (22.2 mmol) of 3-phenylpropylamine, 3.39 ml (40.3
mmol) of diketene and 3.37 g (33.3 mmol) of triethylamine were
heated and stirred in 20 ml of toluene at 80.degree. C. for 3
hours. After saturated aqueous sodium hydrogencarbonate solution
was added, the reaction mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure to obtain the title
compound. The residue was purified by the silica gel chromatography
(hexane/ethyl acetate=3/1) to obtain the title compound.
[0486] Yield: 3.48 g (15.9 mmol) (71%)
[0487] MS (ESI, m/z) 218 (M-H).sup.-
[0488] .sup.1H-NMR (CDCl3): 1.86 (2H, quint), 2.26 (3H, s), 2.66
(2H, t), 3.30 (2H, q), 3.39 (2H, s), 6.96 (1H, br), 7.17-7.21 (3H,
m), 7.26-7.31 (2H, m).
[0489] 2) Synthesis of
2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide:
[0490] 2.22 g (10.1 mmol) of 3-oxo-N-(3-phenylpropyl) butylamide
and 1.77 g (10.1 mmol) of 3,5-dichlorobenzaldehyde were dissolved
in 30 ml of 2-propanol. 86.0 mg (1.01 mmol) of piperidine and 60.7
mg (1.01 mmol) of acetic acid were added and stirred at room
temperature for one day. After the solvent was evaporated under
reduced pressure, ethyl acetate was added thereto. The reaction
mixture was washed with 1 N hydrochloric acid and then with
saturated aqueous sodium hydrogencarbonate solution. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain
the title compound.
[0491] Yield: 2.58 g (6.87 mmol) (68%)
[0492] MS (ESI, m/z) 376 (M).sup.+
[0493] .sup.1 H-NMR (CDCl3): 1.86 (2H, quint), 2.41 (3H, s), 2.61
(2H, t), 3.39 (2H, q), 5.84 (1H, br t), 7.11-7.40 (9H, m).
[0494] 3) Synthesis of
2-(t-butyl)-4-(3,5-dichlorophenyl)-6-methyl-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0495] 100 mg (0.266 mmol) of
2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylp- ropyl) acrylamide was
dissolved in 5 ml of DMF. 54.5 mg (0.399 mmol) of
t-butyl-carbamidine-hydrochloride and 32.7 mg (0.399 mmol) of
sodium acetate were added at room temperature and stirred at
80.degree. C. for one day. After DMF was evaporated under reduced
pressure, the reaction mixture was diluted with ethyl acetate and
washed with saturated aqueous sodium chloride solution. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to
obtain the title compound.
[0496] Yield: 62.2 mg (0.136 mmol) (51%)
[0497] MS (ESI, m/z) 456 (M+H).sup.+ 454 (M-H).sup.-
[0498] .sup.1H-NMR (CDCl3): 1.42 (9H, s), 1.76 (2H, quint), 2.50
(2H, t), 2.58 (3H, s), 3.35 (2H, q), 5.50 (1H, br s), 7.08 (21H,
d), 7.15-7.21 (1H, m), 7.24-7.29 (2H, m) 7.40-7.41 (1H, m), 7.73
(2H, d).
EXAMPLE 62
[0499] Synthesis of
2-cyclopropyl-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phe-
nylpropyl)-5-pyrimidinecarboxamide:
[0500] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
48.1 mg (0.399 mmol) of cyclopropyl-carbamidine-hydrochloride and
32.7 mg (0.399 mmol) of sodium acetate, in the same manner as that
of Example 61.
[0501] Yield: 90.4 mg (0.205 mmol) (77%)
[0502] MS (ESI, m/z) 440 (M+H).sup.+ 438 (M-H).sup.-
[0503] .sup.1H-NMR (CDCl3): 1.06-1.14 (2H, m), 1.17-1.22 (2H, m),
1.73 (2H, quint), 2.22-2.30 (1H, m), 2.48 (2H, t), 2.53 (3H, s),
3.31 (2H, q), 5.48 (1H, br t), 7.06-7.08 (2H, m), 7.15-7.20 (1H,
m), 7.24-7.29 (2H, m), 7.39-7.40 (1H, m), 7.66-7.68 (2H, m).
EXAMPLE 63
[0504] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-(morpholine-4-yl)-N--
(3-phenylpropyl)-5-pyrimidinecarboxamide:
[0505] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
83.8 mg (0.399 mmol) of morpholino-formamidine-hydrochloride and
32.7 mg (0.399 mmol) of sodium acetate, in the same manner as that
of Example 61.
[0506] Yield: 59.2 mg (0.122 mmol) (46%)
[0507] MS (ESI, m/z) 485 (M+H).sup.+ 483 (M-H).sup.-
[0508] .sup.1H-NMR (CDCl3): 1.70 (2H, quint), 2.44-2.49 (5H, m),
3.27 (2H, q), 3.76 (4H, br), 3.87 (4H, br), 5.44 (1H, br), 7.07
(2H, d), 7.15-7.29 (3H, m), 7.37 (1H, s), 7.63 (2H, s).
EXAMPLE 64
[0509] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
pyridine-2-yl)-5-pyrimidinecarboxamide:
[0510] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
62.9 mg (0 399 mmol) of 2-amidinopyridinium hydrochloride and 32.7
mg (0.399 mmol) of sodium acetate, in the same manner as that of
Example 61.
[0511] Yield: 46.5 mg (0.0974 mmol) (37%)
[0512] MS (ESI, m/z) 477 (M+H).sup.+ 475 (M-H)
[0513] .sup.1H-NMR (CDCl3): 1.87 (2H, quint), 2.60 (2H, t), 2.70
(3H, s), 3.44 (2H, q), 6.59 (1H, br t), 7.12-7.21 (3H, m),
7,24-7.30 (2H, m), 7.3, 5-7.41 (2H, m), 7.71 (2H, d), 7.88 (1H,
td), 8.52 (1H, dt), 8.62-8.65 (1H, m).
EXAMPLE 65
[0514] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
pyridine-4-yl)-5-pyrimidinecarboxamide:
[0515] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
62.9 mg (0.399 mmol) of 4-amidinopyridinium hydrochloride and 32.7
mg (0.399 mmol) of sodium acetate, in the same manner as that of
Example 61.
[0516] Yield: 71.8 mg (0.150 mmol) (72%)
[0517] MS (ESI, m/z) 477 (M+H).sup.+ 475 (M-H).sup.-
[0518] .sup.1H-NMR (CDCl3): 1.81 (2H, quint), 2.54 (2H, t), 2.69
(3H, s), 3.40 (2H, q), 6.42 (1H, br t), 7.10-7.12 (2H, m),
7.16-7.21 (1H, m), 7.24-7.30 (2H, m), 7.47 (1H, t), 7.79 (2H, d),
8.24-8.26 (2H, m), 8.61-8.63 (2H, m).
EXAMPLE 66
[0519] Synthesis of
4-methyl-2-(methylthio)-6-(2-naphthyl)-N-(3-phenylprop-
yl)-2-(pyridine-4-yl)-5-pyrimidinecarboxamide:
[0520] The title compound was obtained by using 150 mg (0.420 mmol)
of 2-acetyl-3-(2-naphthyl)-N-(3-phenylpropyl) acrylamide, 87.7 mg
(0.315 mmol) of methylisothiourea-sulfate and 68.9 mg (0.840 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0521] Yield: 44.3 mg (0.10 mmol) (24%)
[0522] MS (ESI, m/z) 427 (M+H).sup.+
[0523] .sup.1H-NMR (CDCl3): 1.52 (2H, quint), 2.22 (2H, t), 2.57
(3H, s), 2.64 (3H, s), 3.22 (2H, q), 5.45 (1H, br t), 6.78-6.81
(2H, m), 7.11-7.18 (3H, m), 7.47-7.57 (2H, m), 7.83-7.91 (4H, m),
8.32 (1H, s).
EXAMPLE 67
[0524] Synthesis of
4-methyl-6-(4-methylphenyl)-2-phenyl-N-(3-phenylpropyl-
)-5-pyrimidinecarboxamide:
[0525] The title compound was obtained by using 200 mg (0.622 mmol)
of 2-acetyl-3-(4-methylphenyl)-N-(3-phenylpropyl) acrylamide, 146
mg (0.932 mmol) of benzamidine hydrochloride and 102 mg (1.24 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0526] Yield: 57.0 mg (0.135 mmol) (23%)
[0527] MS (ESI, m/z) 422 (M+H).sup.+
[0528] .sup.1H-NMR (CDCl3): 1.68 (2H, quint), 2.36 (3H, s), 2.41
(2H, t), 2.68 (3H, s), 3.32 (2H, q), 5.45 (1H, br t), 7.03-7.06
(2H, m), 7.15-7.28 (5H, m), 7.47-7.51 (3H, m), 7.80-8.84 (2H, m),
8.51-8.55 (2H, m).
EXAMPLE 68
[0529] Synthesis of
4-methyl-6-(4-methylphenyl)-2-(methylthio)-N-(3-phenyl-
propyl)-5-pyrimidinecarboxamide:
[0530] The title compound was obtained by using 200 mg (0.622 mmol)
of 2-acetyl-3-(4-methylphenyl)-N-(3-phenylpropyl) acrylamide, 129
mg (0.463 mmol) of methylisothiourea-sulfate and 102 mg (1.24 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0531] Yield: 55.0 mg (0.140 mmol) (22%)
[0532] MS (ESI, m/z) 392 (M+H).sup.+
[0533] .sup.1H-NMR (CDCl3): 1.65 (2H, quint), 2.34 (3H, s), 2.38
(2H, t), 2.54 (3H, s), 2.60 (3H, s), 3.27 (2H, q), 5.39 (1H, br t),
7.01-7.04 (2H, m), 7.15-7.28 (5H, m), 7.68-7.72 (2H, m).
EXAMPLE 69
[0534] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
1H-pyrazole-1-yl)-5-pyrimidinecarboxamide:
[0535] The title compound was obtained by using 80.0 mg (0.213
mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl)
acrylamide, 46.9 mg (0.320 mmol) of
1H-pyrazole-1-carboxamidine-hydrochloride and 26.2 mg (0.320 mmol)
of sodium acetate, in the same manner as that of Example 61.
[0536] Yield: 35.2 mg (0.0755 mmol) (35%)
[0537] MS (ESI, m/z) 466 (M+H).sup.+ 464 M-H).sup.-
[0538] .sup.1H-NMR (CDCl3): 1.79 (2H, quint), 2.53 (2H, t), 2.67
(3H, s), 3.37 (2H, q), 5.80 (1H, br t), 6.51-6.53 (1H, m),
7.09-7.11 (2H, m), 7.16-7.21 (1H, m), 7.24-7.30 (3H, m), 7.45 (1H,
t), 7.74 (2H, d), 7.81-7.82 (1H, m), 8.64-8.65 (1H, m).
EXAMPLE 70
[0539] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-methylamino-N-(3-phe-
nylpropyl)-5-pyrimidinecarboxamide:
[0540] The title compound was obtained by using 80.0 mg (0.213
mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl)
acrylamide, 35.1 mg (0.320 mmol) of 1-methylguanidine-hydrochloride
and 26.2 mg (0.320 mmol) of sodium acetate, in the same manner as
that of Example 61.
[0541] Yield: 23.3 mg (0.0543 mmol) (26%)
[0542] MS (ESI, m/z) 429 (M+H).sup.+ 427 (M-H).sup.-
[0543] .sup.1H-NMR (CDCl3): 1.70 (2H, quint), 2.42-2.49 (5H, m),
3.04 (3H, d), 3.27 (2H, q), 5.38 (1H, t), 7.07-7.10 (2H, m),
7.15-7.20 (1H, m), 7.24-7.29 (2H, m), 7.37-7.42 (1H, m), 7.64 (2H,
d), 8.03 (1H, d).
EXAMPLE 71
[0544] Synthesis of
4-(3,5-dichlorophenyl)-2-dimethylamino-6-methyl-N-(3-p-
henylpropyl)-5-pyrimidinecarboxamide:
[0545] The title compound was obtained by using 80.0 mg (0.213
mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl)
acrylamide, 87.1 mg (0.320 mmol) of
1,1-dimethylguanidine-hydrochloride and 26.2 mg (0.320 mmol) of
sodium acetate, in the same manner as that of Example 61.
[0546] Yield: 45.1 mg (0.102 mmol) (48%)
[0547] MS (ESI, m/z) 443 (M+H).sup.+ 441 (M-H).sup.-
[0548] .sup.1H-NMR (CDCl3): 1.70 (2H, quint), 2.41 (5H, m),
3.23-3.30 (8H, m), 5.38 (1H, br t), 7.07-7.09 (2H, m), 7.15-7.29
(3H, m), 7.36 (1H, t), 7.64 (2H, d).
EXAMPLE 72
[0549] Synthesis of
4-(3,5-dichlorophenyl)-2-(3,5-dimethyl-1H-pyrazole-1-y-
l)-6-methyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide:
[0550] The title compound was obtained by using 55.5 mg (0.148
mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl)
acrylamide, 44.5 mg (0.221 mmol) of
3,5-dimethylpyrazole-1-carboxamidine-nitrate and 26.2 mg (0.320
mmol) of sodium acetate, in the same manner as that of Example
61.
[0551] Yield: 30.9 mg (0.0625 mmol) (43%)
[0552] MS (ESI, m/z) 496 (M+H).sup.+ 494 (M-H).sup.-
[0553] .sup.1H-NMR (CDCl3): 1.84 (2H, quint), 2.23 (2H, s), 2.57
(2H, t), 2.65 (6H, s), 3.39 (2H, q), 6.06 (1H, s), 6.25 (1H, br),
7.10-7.20 (3H, m), 7.25-7.29 (2H, m), 7.43-7.44 (1H, m), 7.69-7.70
(2H, m).
EXAMPLE 73
[0554] Synthesis of
4-(3-chlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(pipe-
ridine-1-yl)-5-pyrimidinecarboxamide:
[0555] 44.0 mg (0.107 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)--
N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of
dichloromethane. 36.9 mg (0.213 mmol) of mCPBA (m-chloroperbenzoic
acid) was added thereto at 0.degree. C. and stirred at the same
temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite
solution was added thereto at the same temperature and stirred for
30 minutes heating to room temperature. After the reaction mixture
was diluted with dichloromethane, the organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
obtained residue was dissolved in 5 ml of toluene and 91.1 mg (1.07
mmol) of piperidine was added at room temperature and stirred at
80.degree. C. for 6 hours. After concentration under reduced
pressure, the obtained residue was diluted with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride
solution and dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to
obtain the title compound.
[0556] Yield: 38.2 mg (0.0851 mmol) (80%)
[0557] MS (ESI, m/z) 449 (M+H).sup.+ 447 (M-H).sup.-
[0558] .sup.1H-NMR (CDCl3): 1.57-1.69 (8H, m), 2.38-2.44 (5H, m),
3.23 (2H, q), 3.86 (4H, t), 5.28 (1H, br t), 7.04-7.06 (2H, m),
7.14-7.20 (1H, m), 7.23-7.30 (2H, m), 7.32-7.38 (2H, m), 7.62 (1H,
dt), 7.74-7.76 (1H, m).
EXAMPLE 74
[0559] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
trifluoromethyl)-5-pyrimidinecarboxamide:
[0560] The title compound was obtained by using 80.0 mg (0.213
mmol) of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl)
acrylamide, 35.9 mg (0.320 mmol) of trifluoroacetamidine and 26.2
mg (0.320 mmol) of sodium acetate, in the same manner as that of
Example 61.
[0561] Yield: 25.1 mg (0.0536 mmol) (25%)
[0562] MS (ESI, m/z) 466 (M-H).sup.-
[0563] .sup.1H-NMR (CDCl3): 1.78 (2H, quint), 2.51 (2H, t), 2.71
(3H, s), 3.38 (2H, q), 5.54 (1H, br t), 7.07-7.09 (2H, m),
7.16-7.21 (1H, m), 7.23-7.30 (2H, m), 7.48 (1H, t), 7.76 (2H,
d).
EXAMPLE 75
[0564] Synthesis of
4-(4-isopropylphenyl)-2,6-dimethyl-N-(3-phenylpropyl)--
5-pyrimidinecarboxamide:
[0565] The title compound was obtained by using 150 mg (0.429 mmol)
of 2-acetyl-3-(4-isopropylphenyl)-N-(3-phenylpropyl) acrylamide,
61.0 mg (0.645 mmol) of acetamidine hydrochloride and 70.5 mg
(0.859 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0566] Yield: 44.3 mg (0.114 mmol) (26%)
[0567] MS (ESI, m/z) 388 (M+H).sup.+
[0568] .sup.1H-NMR (CDCl3): 1.19 (6H, d), 1.61 (2H, quint), 2.37
(2H, t), 2.57 (3H, s), 2.74 (3H, s), 2.89 (1H, sept), 3.26 (2H, q),
5.38 (1H, br t), 7.02 (2H, d), 7.13-7.30 (5H, m), 7.69 (2H, d).
EXAMPLE 76
[0569] Synthesis of
4-(4-isopropylphenyl)-6-methyl-2-(methylthio)-N-(3-phe-
nylpropyl)-5-pyrimidinecarboxamide:
[0570] The title compound was obtained by using 150 mg (0.429 mmol)
of 2-acetyl-3-(4-isopropylphenyl)-N-(3-phenylpropyl) acrylamide,
90.0 mg (0.323 mmol) of methylisothiourea-sulfate and 70.5 mg
(0.859 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0571] Yield: 124 mg (0.296 mmol) (70%)
[0572] MS (ESI, m/z) 420 (M+H).sup.+
[0573] .sup.1H-NMR (CDCl3): 1.20 (6H, d), 1.62 (2H, quint), 2.38
(2H, t), 2.53 (3H, s), 2.60 (3H, s), 2.89 (1H, sept), 3.26 (2H, q),
5.40 (1H, br t), 7.01-7.04 (2H, m), 7.13-7.29 (5H, m), 7.71-7.75
(2H, m).
EXAMPLE 77
[0574] Synthesis of
4-(4-t-butylphenyl)-2,6-dimethyl-N-(3-phenylpropyl)-5--
pyrimidinecarboxamide:
[0575] The title compound was obtained by using 150 mg (0.413 mmol)
of 2-acetyl-3-(4-t-butylphenyl)-N-(3-phenylpropyl) acrylamide, 58.1
mg (0.615 mmol) of acetamidine hydrochloride and 67.3 mg (0.820
mmol) of sodium acetate, in the same manner as that of Example
1.
[0576] Yield: 73.8 mg (0.184 mmol) (44%)
[0577] MS (ESI, m/z) 402 (M+H).sup.+
[0578] .sup.1H-NMR (CDCl3): 1.25 (9H, s), 1.60 (2H, quint), 2.36
(2H, t), 2.57 (3H, s), 2.73 (3H, s), 3.26 (2H, q), 5.42 (1H, br t),
7.01-7.03 (2H, m), 7.13-7.25 (3H, m), 7.42-7.46 (2H, m), 7.66-7.71
(2H, m).
EXAMPLE 78
[0579] Synthesis of
4-(4-t-butylphenyl)-6-methyl-2-(methylthio)-N-(3-pheny-
lpropyl)-5-pyrimidinecarboxamide:
[0580] The title compound was obtained by using 150 mg (0.413 mmol)
of 2-acetyl-3-(4-t-butylphenyl)-N-(3-phenylpropyl) acrylamide, 85.6
mg (0.307 mmol) of methylisothiourea-sulfate and 67.3 mg (0.820
mmol) of sodium acetate, in the same manner as that of Example
1.
[0581] Yield: 107 mg (0.247 mmol) (61%)
[0582] MS (ESI, m/z) 434 (M+H).sup.+
[0583] .sup.1H-NMR (CDCl3): 1.27 (9H, s), 1.61 (2H, quint), 2.38
(2H, t), 2.53 (3H, s), 2.60 (3H, s), 3.25 (2H, q), 5.45 (1H, br t),
7.01-7.04 (2H, m), 7.13-7.26 (3H, m), 7.41-7.45 (2H, m), 7.71-7.76
(2H, m).
EXAMPLE 79
[0584] Synthesis of
4-(3,5-dichlorophenyl)-2-isobutylamino-6-methyl-N-(3-p-
henylpropyl)-5-pyrimidinecarboxamide:
[0585] 83.8 mg (0.203 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)--
N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of
dichloromethane. 70.2 mg (0.407 mmol) of mCPBA (m-chloroperbenzoic
acid) was added thereto at 0.degree. C. and stirred at the same
temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite
solution was added thereto at the same temperature and stirred for
30 minutes heating to room temperature. After the reaction mixture
was diluted with dichloromethane, the organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
obtained residue was dissolved in 5 ml of toluene and excessive
amounts of 74.2 mg (1.02 mmol) of isobutylamine was added at room
temperature and stirred at 80.degree. C. for 6 hours. After
concentration under reduced pressure, the obtained residue was
diluted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 1/1) to obtain the title compound.
[0586] Yield: 57.5 mg (0.132 mmol) (65%)
[0587] MS (ESI, m/z) 437 M+H).sup.+ 435 (M-H).sup.-
[0588] .sup.1H-NMR (CDCl3): 0.97 (6H, d), 1.64 (2H, quint), 1.89
(1H, sept), 2.38-2.43 (5H, m), 3.23 (2H, q), 3.32 (2H, t), 5.31
(2H, br), 7.04-7.07 (2H, m), 7.14-7.38 (5H, m), 7.60 (1H, br d),
7.73 (1H, br s).
EXAMPLE 80
[0589] Synthesis of
4-(3-chlorophenyl)-2-methoxy-6-methyl-N-(3-phenylpropy-
l)-5-pyrimidinecarboxamide:
[0590] 62.8 mg (0.153 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)--
N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of
dichloromethane. 52.7 mg (0.305 mmol) of mCPBA (m-chloroperbenzoic
acid) was added thereto at 0.degree. C. and stirred at the same
temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite
solution was added thereto at the same temperature and stirred for
30 minutes heating to room temperature. After the reaction mixture
was diluted with dichloromethane, the organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
obtained residue was dissolved in 5 ml of methanol and excessive
amounts of 295 mg (1 63 mmol) of sodium methoxide (28% methanol
solution) was added at room temperature and stirred at 60.degree.
C. for 6 hours. After concentration under reduced pressure, the
obtained residue was diluted with ethyl acetate. The organic layer
was washed with saturated aqueous sodium chloride solution and
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by the silica gel
chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the
title compound.
[0591] Yield: 42.0 mg (0.106 mmol) (70%)
[0592] MS (ESI, m/z) 396 (M+H).sup.+ 394 (M-H).sup.-
[0593] .sup.1 H-NMR (CDCl3): 1.69 (2H, quint), 2.44 (2H, t), 2.54
(3H, s), 3.28 (2H, q), 4.05 (3H, s), 5.48 (1H, br t), 7.04-7.07
(2H, m), 7.14-7.20 (1H, m), 7.23-7.28 (2H, m), 7.34 (1H, t),
7.39-7.43 (1H, m), 7.68 (1H, dt), 7.81 (1H, t).
EXAMPLE 81
[0594] Synthesis of
2,4-dimethyl-6-(2-naphthyl)-N-(3-phenylpropyl)-5-pyrim-
idinecarboxamide:
[0595] The title compound was obtained by using 150 mg (0.420 mmol)
of 2-acetyl-3-(2-naphthyl)-N-(3-phenylpropyl) acrylamide, 59.6 mg
(0.630 mmol) of acetamidine hydrochloride and 68.9 mg (0.840 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0596] Yield: 29.8 mg (0.0753 mmol) (18%)
[0597] MS (ESI, m/z) 396 (M+H).sup.+
[0598] .sup.1H-NMR (CDCl3): 1.51 (2H, quint), 2.21 (2H, t), 2.62
(3H, s), 2.79 (3H, s), 3.23 (2H, q), 5.43 (1H, br t), 6.77-6.80
(2H, m), 7.10-7.18 (3H, m), 7.47-7.57 (2H, m), 7.83-7.92 (4H, m),
8.30 (1H, s).
EXAMPLE 82
[0599] Synthesis of
2,4-dimethyl-6-(1-naphthyl)-N-(3-phenylpropyl)-5-pyrim-
idinecarboxamide:
[0600] The title compound was obtained by using 150 mg (0.420 mmol)
of 2-acetyl-3-(1-naphthyl)-N-(3-phenylpropyl) acrylamide, 59.6 mg
(0.630 mmol) of acetamidine hydrochloride and 68.9 mg (0.840 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0601] Yield: 24.7 mg (0.0625 mmol) (15%)
[0602] MS (ESI, m/z) 396 (M+H).sup.+
[0603] .sup.1H-NMR (CDCl3): 1.01 (2H, quint), 1.93 (2H, t), 2.66
(3H, s), 2.80 (3H, s), 2.93 (2H, q), 5.16 (1H, br t), 6.76-6.79
(2H, m), 7.11-7.23 (3H, m), 7.46-7.53 (4H, m), 7.66-7.70 (1H, m),
7.82-7.87 (2H, m).
EXAMPLE 83
[0604] Synthesis of
4-methyl-2-(methylthio)-6-(1-naphthyl)-N-(3-phenylprop-
yl)-5-pyrimidinecarboxamide:
[0605] The title compound was obtained by using 150 mg (0.420 mmol)
of 2-acetyl-3-(1-naphthyl)-N-(3-phenylpropyl) acrylamide, 87.7 mg
(0.315 mmol) of methylisothiourea-sulfate and 68.9 mg (0.840 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0606] Yield: 37.5 mg (0.0877 mmol) (21%)
[0607] MS (ESI, m/z) 428 (M+H).sup.+
[0608] .sup.1H-NMR (CDCl3): 1.01 (2H, quint), 1.94 (2H, t), 2.56
(3H, s), 2.62 (3H, s), 2.91 (2H, q), 5.11 (1H, br t), 6.77-6.80
(2H, m), 7.11-7.23 (3H, m), 7.46-7.54 (4H, m), 7.76-7.90 (3H,
m).
EXAMPLE 84
[0609] Synthesis of
2,6-dimethyl-4-(3,4-dimethylphenyl)-N-(3-phenylpropyl)-
-5-pyrimidinecarboxamide:
[0610] The title compound was obtained by using 150 mg (0.447 mmol)
of 2-acetyl-3-(3,4-dimethylphenyl)-N-(3-phenylpropyl) acrylamide,
63.8 mg (0.675 mmol) of acetamidine hydrochloride and 73.8 mg
(0.900 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0611] Yield: 41.7 mg (0.112 mmol) (24%)
[0612] MS (ESI, m/z) 374 (M+H).sup.+
[0613] .sup.1 H-NMR (CDCl3): 1.56-1.66 (2H, m), 2.21 (3H, s), 2.24
(3H, s), 2.34 (2H, t), 2.57 (3H, s), 2.74 (3H, s), 3.27 (2H, q),
5.42 (1H, br t), 7.00-7.02 (2H, m), 7.14-7.28 (4H, m), 7.46-7.53
(2H, m).
EXAMPLE 85
[0614] Synthesis of
4-(3,4-dimethylphenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0615] The title compound was obtained by using 150 mg (0.447 mmol)
of 2-acetyl-3-(3,4-dimethylphenyl)-N-(3-phenylpropyl) acrylamide,
94.0 mg (0.338 mmol) of methylisothiourea-sulfate and 73.8 mg
(0.900 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0616] Yield: 89.7 mg (0.221 mmol) (49%)
[0617] MS (ESI, m/z) 406 (M+H).sup.+
[0618] .sup.1H-NMR (CDCl3): 1.62 (2H, quint), 2.22 (3H, s), 2.23
(3H, s), 2.35 (2H, t), 2.52 (3H, s), 2.59 (3H, s), 3.26 (2H, q),
5.49 (1H, br t), 7.00-7.03 (2H, m), 7.15-7.28 (4H, m), 7.50-7.54
(2H, m).
EXAMPLE 86
[0619] Synthesis of
4-(3-chlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(pipe-
razine-1-yl)-5-pyrimidinecarboxamide:
[0620] 83.8 mg (0.203 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)--
N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of
dichloromethane. 70.2 mg (0.407 mmol) of mCPBA (m-chloroperbenzoic
acid) was added thereto at 0.degree. C. and stirred at the same
temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite
solution was added thereto at the same temperature and stirred for
30 minutes heating to room temperature. After the reaction mixture
was diluted with dichloromethane, the organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
obtained residue was dissolved in 5 ml of toluene and excessive
amounts of 74.2 mg (1.02 mmol) of isobutylamine was added at room
temperature and stirred at 80.degree. C. for 6 hours. After
concentration under reduced pressure, the obtained residue was
diluted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the basic silica gel chromatography
(hexane/ethyl acetate=10/1 to 1/1) to obtain the title
compound.
[0621] Yield: 82.7 mg (0.184 mmol) (91%)
[0622] MS (ESI, m/z) 450 (M+H).sup.+
[0623] .sup.1H-NMR (CDCl3): 1.64 (2H, quint), 2.38-2.44 (5H, m),
2.91 (4H, t), 3.23 (2H, q), 3.87 (4H, t), 5.33 (1H, br t),
7.04-7.06 (2H, m), 7.14-7.38 (5H, m), 7.60-7.63 (1H, m), 7.74-7.76
(1H, m).
[0624]
EXAMPLE 87
[0625] Synthesis of
4-(3-chlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(thio-
phene-2-yl)-5-pyrimidinecarboxamide:
[0626] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
64.9 mg (0.399 mmol) of 2-amidinothiophene hydrochloride and 32.7
mg (0.399 mmol) of sodium acetate, in the same manner as that of
Example 61.
[0627] Yield: 108 mg (0.224 mmol) (84%)
[0628] MS (ESI, m/z) 482 (M+H).sup.+ 480 (M-H).sup.-
[0629] .sup.1H-NMR (CDCl3): 1.79 (2H, quint), 2.50 (2H, t), 2.62
(3H, s), 3.34 (2H, q), 5.55 (1H, br t), 7.07-7.10 (2H, m),
7.15-7.21 (2H, m), 7.24-7.30 (2H, m), 7.43 (1H, t), 7.51-7.53 (1H,
m), 7.76 (2H, d), 8.07-8.09 (1H, m).
EXAMPLE 88
[0630] Synthesis of
4-(3-chlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-[([pi-
peridine-1-yl) ethoxy]-5-pyrimidinecarboxamide:
[0631] 185 mg (0.254 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-N-
-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml of
dichloromethane. 87.7 mg (0.508 mmol) of mCPBA (m-chloroperbenzoic
acid) was added thereto at 0.degree. C. and stirred at the same
temperature for 6 hours. 1 ml of saturated aqueous sodium bisulfite
solution was added thereto at the same temperature and stirred for
30 minutes heating to room temperature. After the reaction mixture
was diluted with dichloromethane, the organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
obtained residue was dissolved in 5 ml of DMF. Alkoxide prepared
from 146 mg (1.13 mmol) of 1-piperidine ethanol and 45.2 mg (1.13
mmol) of sodium hydride (60% oily substance) was added at 0.degree.
C. and stirred heating to room temperature for 1 hour. After
concentration under reduced pressure, the obtained residue was
diluted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the basic silica gel chromatography
(hexane/ethyl acetate=5/1 to 1/1) to obtain the title compound.
[0632] Yield: 78.1 mg (0.158 mmol) (62%)
[0633] MS (ESI, m/z) 493 (M+H).sup.+
[0634] .sup.1H-NMR (CDCl3): 1.40-1.48 (2H, m), 1.54-1.62 (4H, m),
1.69 (2H, quint), 2.41-2.54 (7H, m), 2.80 (2H, t), 3.28 (2H, q),
3.58 (2H, t), 4.56 (2H, t), 5.45 (1H, br t), 7.04-7.06 (2H, m),
7.12-7.42 (5H, m), 7.66-7.69 (1H, m), 7.80-7.82 (1H, m).
EXAMPLE 89
[0635] Synthesis of
4-(3,4-dichlorophenyl)-2-methoxy-6-methyl-N-(3-phenylp-
ropyl)-5-pyrimidinecarboxamide:
[0636] 131 mg (0.293 mmol) of
4-(3,4-dichlorophenyl)-6-methyl-2-(methylthi-
o)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5 ml
of dichloromethane. 101 mg (0.586 mmol) of mCPBA
(m-chloroperbenzoic acid) was added thereto at 0.degree. C. and
stirred at the same temperature for 6 hours. 1 ml of saturated
aqueous sodium bisulfite solution was added thereto at the same
temperature and stirred for 30 minutes heating to room temperature.
After the reaction mixture was diluted with dichloromethane, the
organic layer was washed with saturated aqueous sodium chloride
solution and dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The obtained residue was
dissolved in 5 ml of methanol and excessive amounts of 565 mg (2.93
mmol) of sodium methoxide (28% methanol solution) was added at room
temperature and stirred at 60.degree. C. for 6 hours. After
concentration under reduced pressure, the obtained residue was
diluted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 1/1) to obtain the title compound.
[0637] Yield: 20.8 mg (0.0483 mmol) (17%)
[0638] MS (ESI, m/z) 430 (M+H).sup.+ 428 (M-H).sup.-
[0639] .sup.1H-NMR (CDCl3): 1.74 (2H, quint), 2.47-2.54 (5H, m),
3.31 (2H, q), 4.05 (3H, s), 5.55 (1H, br), 7.05-7.08 (2H, m),
7.15-7.29 (3H, m), 7.48 (1H, d), 7.64-7.68 (1H, m), 7.94-7.95 (1H,
m).
EXAMPLE 90
[0640] Synthesis of
4-(3-chloro-4-methoxyphenyl)-2-cyclopropyl-6-methyl-N--
(3-phenylpropyl)-5-pyrimidinecarboxamide:
[0641] The title compound was obtained by using 150 mg (0.419 mmol)
of 2-acetyl-3-(3-chloro-4-methoxyphenyl)-N-(3-phenylpropyl)
acrylamide, 76.0 mg (0.629 mmol) of cyclopropyl-carbamidine
hydrochloride and 68.9 mg (0.840 mmol) of sodium acetate, in the
same manner as that of Example 1.
[0642] Yield: 54.7 mg (0.125 mmol) (31%)
[0643] MS (ESI, m/z) 436 (M+H).sup.+
[0644] .sup.1H-NMR (CDCl3): 1.04-1.11 (2H, m), 1.17-1.22 (2H, m),
1.72 (2H, quint), 2.23-2.32 (1H, m), 2.45 (2H, t), 2.54 (3H, s),
3.32 (2H, q), 3.85 (3H, s), 5.47 (1H, br s), 6.90 (1H, d),
7.04-7.07 (1H, m), 7.15-7.20 (1H, m), 7.23-7.26 (3H, m), 7.70 (1H,
dd), 7.88 (1H, d).
EXAMPLE 91
[0645] Synthesis of
4-(3-chloro-4-methoxyphenyl)-6-methyl-2-(methylthio)-N-
-(3-phenylpropyl)-5-pyrimidinecarboxamide:
[0646] The title compound was obtained by using 150 mg (0.419 mmol)
of 2-acetyl-3-(3-chloro-4-methoxyphenyl)-N-(3-phenylpropyl)
acrylamide, 87.7 mg (0.313 mmol) of methylisothiourea-sulfate and
68.9 mg (0.840 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0647] Yield: 80.6 mg (0.182 mmol) (43%)
[0648] MS (ESI, m/z) 442 (M+H).sup.+
[0649] .sup.1H-NMR (CDCl3): 1.72 (2H, quint), 2.46 (2H, t), 2.51
(3H, s), 2.59 (3H, s), 3.31 (2H, q), 3.85 (3H, s), 5.60 (1H, br t),
6.90 (1H, d), 7.04-7.07 (2H, m), 7.14-7.28 (3H, m), 7.72 (1H, dd),
7.90 (1H, d).
EXAMPLE 92
[0650] Synthesis of
2-cyclopropyl-4-(2,4-dimethylphenyl)-6-methyl-N-(3-phe-
nylpropyl)-5-pyrimidinecarboxamide:
[0651] The title compound was obtained by using 150 mg (0.467 mmol)
of 2-acetyl-3-(2,4-dimethylphenyl)-N-(3-phenylpropyl) acrylamide,
84.4 mg (0.700 mmol) of cyclopropyl-carbamidine hydrochloride and
77.1 mg (0.940 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0652] Yield: 92.9 mg (0.233 mmol) (49%)
[0653] MS (ESI, m/z) 400 (M+H).sup.+
[0654] .sup.1H-NMR (CDCl3): 1.01-1.07 (2H, m), 1.13-1.18 (2H, m),
1.37-1.47 (2H, m), 2.22-2.30 (9H, m), 2.55 (3H, s), 3.15 (2H, q),
5.22 (1H, br t), 6.97-7.05 (3H, m), 7.13-7.28 (5H, m).
EXAMPLE 93
[0655] Synthesis of
4-(2,4-dimethylphenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0656] The title compound was obtained by using 150 mg (0.467 mmol)
of 2-acetyl-3-(2,4-dimethylphenyl)-N-(3-phenylpropyl) acrylamide,
97.4 mg (0.350 mmol) of methylisothiourea-sulfate and 77.1 mg
(0.940 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0657] Yield: 92.9 mg (0.229 mmol) (49%)
[0658] MS (ESI, m/z) 406 (M+H).sup.+
[0659] .sup.1H-NMR (CDCl3): 1.43 (2H, quint), 2.23-2.30 (8H, m),
2.55 (3H, s), 2.57 (3H, s), 3.15 (2H, q), 5.15 (1H, br s),
7.01-7.06 (4H, m), 7.15-7.20 (2H, m), 7.24-7.28 (2H, m).
EXAMPLE 94
[0660] Synthesis of
4-(2-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenyl-
propyl)-5-pyrimidinecarboxamide:
[0661] The title compound was obtained by using 100 mg (0.293 mmol)
of 2-acetyl-3-(2-chlorophenyl)-N-(3-phenylpropyl) acrylamide, 60.5
mg (0.217 mmol) of methylisothiourea-sulfate and 47.6 mg (0.580
mmol) of sodium acetate, in the same manner as that of Example
1.
[0662] Yield: 45.6 mg (0.111 mmol) (38%)
[0663] MS (ESI, m/z) 412 (M+H).sup.+
[0664] .sup.1H-NMR (CDCl3): 1.45 (2H, quint), 2.33 (2H, t), 2.56
(3H, s), 2.57 (3H, s), 3.15 (2H, q), 5.59 (1H, br t), 7.02-7.06
(2H, m), 7.15-7.37 (6H, m), 7.40-7.45 (1H, m).
EXAMPLE 95
[0665] Synthesis of
4-(3,5-dichloro-4-methoxyphenyl)-6-methyl-2-(methylthi-
o)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide:
[0666] The title compound was obtained by using 100 mg (0.246 mmol)
of 2-acetyl-3-(3,5-dichloro-4-methoxyphenyl)-N-(3-phenylpropyl)
acrylamide, 52.2 mg (0.188 mmol) of methylisothiourea-sulfate and
41.0 mg (0.500 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0667] Yield: 57.8 mg (0.121 mmol) (48%)
[0668] MS (ESI, m/z) 476 (M+H).sup.+
[0669] .sup.1H-NMR (CDCl3): 1.75 (2H, quint), 2.48-2.53 (5H, m),
2.60 (3H, s), 3.34 (2H, q), 3.84 (3H, s), 5.52 (1H, br t),
7.07-7.10 (2H, m), 7.14-7.28 (3H, m), 7.77 (2H, s).
EXAMPLE 96
[0670] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-phenoxy-N-(3-phenylp-
ropyl)-5-pyrimidinecarboxamide:
[0671] 1) Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-- N-(3-phenyl
propyl)-5-pyrimidinecarboxamide:
[0672] 1.41 g (3.15 mmol) of
4-(3,5-dichlorophenyl)-6-methyl-2-(methylthio-
)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 20 ml
of dichloromethane. 1.09 g (6.30 mmol) of mCPBA (m-chloroperbenzoic
acid) was added thereto at 0.degree. C. and stirred at the same
temperature for 12 hours. 1 ml of saturated aqueous sodium
bisulfite solution was added thereto at the same temperature and
stirred for 30 minutes heating to room temperature. After the
reaction mixture was diluted with dichloromethane, the organic
layer was washed with saturated aqueous sodium chloride solution
and dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by the silica gel
chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the
title compound.
[0673] Yield: 911 mg (1.90 mmol) (61% )
[0674] MS (ESI, m/z) 476 (M-H).sup.-
[0675] .sup.1H-NMR (CDCl3): 1.80 (2H, quint), 2.51 (2H, t), 2.72
(3H, s), 3.26 (3H, s), 3.37 (2H, q), 6.52 (1H, t), 7.09-7.12 (2H,
m), 7.16-7.21 (1H, m), 7.25-7.30 (2H, m), 7.46 (1H, t), 7.78 (1H,
d).
[0676] 2) Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-phenoxy-N-(3-phen-
ylpropyl)-5-pyrimidinecarboxamide:
[0677] 39.3 mg (0.0798 mmol) of phenol was dissolved in DMF. 16.7
mg (0.418 mmol) of sodium hydride (60% oily substance) was added at
0.degree. C. and stirred at the same temperature for 30 minutes.
100 mg (0.209 mmol) of
4-(3,5-dichlorophenyl)-6-methyl-2-methylsulfonyl-N-(3-phe-
nylpropyl)-5-pyrimidinecarboxamide was added at the same
temperature and stirred heating to room temperature for 12 hours.
After concentration under reduced pressure, the obtained residue
was diluted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 1/1) to obtain the title compound.
[0678] Yield: 34.1 mg (1.90 mmol) (33%)
[0679] MS (ESI, m/z) 492 (M+H).sup.+ 490 (M-H).sup.-
[0680] .sup.1H-NMR (CDCl3): 1.76 (2H, quint), 2.47-2.54 (5H, m),
3.34 (2H, q), 5.52 (1H, br t), 7.06-7.10 (2H, m), 7.17-7.29 (6H,
m), 7.39-7.45 (3H, m), 7.65 (2H, d).
EXAMPLE 97
[0681] Synthesis of
4-methyl-6-(2-methylphenyl)-2-(methylthio)-N-(3-phenyl-
propyl)-5-pyrimidinecarboxamide:
[0682] The title compound was obtained by using 150 mg (0.467 mmol)
of 2-acetyl-3-(2-methylphenyl)-N-(3-phenylpropyl) acrylamide, 98.1
mg (0.705 mmol) of methylisothiourea-sulfate and 77.1 mg (0.940
mmol) of sodium acetate, in the same manner as that of Example
1.
[0683] Yield: 99.8 mg (0.255 mmol) (55%)
[0684] MS (ESI, m/z) 392 (M+H).sup.+
[0685] .sup.1H-NMR (CDCl3): 1.42 (2H, quint), 2.27-2.32 (5H, m),
2.56 (3H, s), 2.57 (3H, s), 3.12 (2H, q), 5.20 (1H, br t),
7.01-7.04 (1H, m), 7.17-7.31 (8H, m).
EXAMPLE 98
[0686] Synthesis of
4-(4-methoxy-3-methylphenyl)-6-methyl-2-(methylthio)-N-
-(3-phenylpropyl)-5-pyrimidinecarboxamide:
[0687] The title compound was obtained by using 150 mg (0.427 mmol)
of 2-acetyl-3-(4-methoxy-3-methylphenyl)-N-(3-phenylpropyl)
acrylamide, 90.0 mg (0.323 mmol) of methylisothiourea-sulfate and
70.5 mg (0.859 mmol) of sodium acetate, in the same manner as that
of Example 1.
[0688] Yield: 91.2 mg (0.216 mmol) (51%)
[0689] MS (ESI, m/z) 422 (M+H).sup.+
[0690] 1H-NMR (CDCl3): 1.67 (2H, quint), 2.22 (3H, s), 2.40 (2H,
t), 2.52 (3H, s), 2.61 (3H, s), 3.29 (2H, q), 3.79 (3H, s), 5.43
(1H, br t), 6.82 (1H, d), 7.01-7.04 (2H, m), 7.14-7.28 (3H, m),
7.62-7.68 (2H, m).
EXAMPLE 99
[0691] Synthesis of
4-(3,5-dichlorophenyl)-2-isopropyl-6-methyl-N-(3-pheny-
lpropyl)-5-pyrimidinecarboxamide:
[0692] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
48.9 mg (0.399 mmol) of isopropyl-carbamidine hydrochloride and
43.6 mg (0.532 mmol) of sodium acetate, in the same manner as that
of Example 61.
[0693] Yield: 28.0 mg (0.0663 mmol) (24%)
[0694] MS (ESI, m/z) 442 (M+H).sup.+ 440 (M-H).sup.-
[0695] .sup.1H-NMR (CDCl3): 1.36 (6H, d), 1.75 (2H, quint), 2.49
(2H, t), 2.58 (3H, s), 3.22 (1H, quint), 3.34 (2H, q), 5.49 (1H, br
t), 7.07-7.09 (2H, m), 7.15-7.20 (1H, m), 7.24-7.29 (3H, m),
7.40-7.41 (1H, m), 7.70-7.71 (2H, m).
EXAMPLE 100
[0696] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-(2-methyl-1,3-thiazo-
le-4-yl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide:
[0697] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
70.9 mg (0.399 mmol) of 2-methylthiazole-4-carbamidine
hydrochloride and 43.6 mg (0.532 mmol) of sodium acetate, in the
same manner as that of Example 61.
[0698] Yield: 65.0 mg (0.131 mmol) (49%)
[0699] MS (ESI, m/z) 497 (M+H).sup.+495 (M-H).sup.-
[0700] .sup.1H-NMR (CDCl3): 1.83 (2H, quint), 2.56 (2H, t), 2.66
(3H, s), 2.71 (3H, s), 3.39 (2H, q), 6.23 (1H, br t), 7.10-7.20
(3H, m), 7.23-7.29 (2H, m), 7.42 (1H, t), 7.72 (2H, d), 8.25 (1H,
s).
EXAMPLE 101
[0701] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-phenoxymethyl-N-(3-p-
henylpropyl)-5-pyrimidinecarboxamide:
[0702] The title compound was obtained by using 100 mg (0.266 mmol)
of 2-acetyl-3-(3,5-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
88.8 mg (0.399 mmol) of 2-phenoxyacetamidine hydrochloride and 43.6
mg (0.532 mmol) of sodium acetate, in the same manner as that of
Example 61.
[0703] Yield: 100 mg (0.198 mmol) (75%)
[0704] MS (ESI, m/z) 506 (M+H).sup.+ 504 (M-H).sup.-
[0705] .sup.1H-NMR (CDCl3): 1.76 (2H, quint), 2.49 (2H, t), 2.63
(3H, s), 3.35 (2H, q), 5.32 (2H, s), 5.51 (1H, br t), 6.95-7.09
(5H, m), 7.15-7.20 (1H, m), 7.24-7.33 (5H, m), 7.42 (1H, t), 7.67
(2H, d).
EXAMPLE 102
[0706] Synthesis of
4-(3,5-dichlorophenyl)-2-ethoxy-6-methyl-N-(3-phenylpr-
opyl)-5-pyrimidinecarboxamide:
[0707] 100 mg (0.209 mmol) of
4-3,5-dichlorophenyl)-6-methyl-2-(methylsulf-
onyl-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 5
ml of DMF. 28.4 mg (0.418 mmol) of sodium ethoxide was added at
0.degree. C. and stirred heating to room temperature for 12 hours.
After concentration under reduced pressure, the obtained residue
was diluted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 1/1) to obtain the title compound.
[0708] Yield: 22.2 mg (0.0500 mmol) (24%)
[0709] MS (ESI, m/z) 444 (M+H).sup.+ 442 (M-H).sup.-
[0710] .sup.1H-NMR (CDCl3): 1.45 (3H, t), 1.74 (2H, quint), 2.49
(2H, t), 2.54 (3H, s), 3.32 (2H, q), 4.48 (2H, q), 5.52 (1H, br t),
7.07-7.09 (2H, m), 7.15-7.20 (1H, m), 7.23-7.29 (2H, m), 7.40-7.42
(1H, m), 7.69 (2H, d).
EXAMPLE 103
[0711] Synthesis of
2-ethyl-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpro-
pyl)-5-pyrimidinecarboxamide:
[0712] 1) Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)--
N-(3-phenylpropyl)-5-pyrimidinecarboxamide
[0713] 1.41 g (3.15 mmol) of
4-(3,5-dichlorophenyl)-6-methyl-2-(methylthio-
)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 20 ml
of dichloromethane. 1.09 g (6.30 mmol) of mCPBA (m-chloroperbenzoic
acid) was added thereto at 0.degree. C. and stirred at the same
temperature for 12 hours. 1 ml of saturated aqueous sodium
bisulfite solution was added thereto at the same temperature and
stirred for 30 minutes heating to room temperature. After the
reaction mixture was diluted with dichloromethane, the organic
layer was washed with saturated aqueous sodium chloride solution
and dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by the silica gel
chromatography (hexane/ethyl acetate=5/1 to 1/1) to obtain the
title compound.
[0714] Yield: 911 mg (1.90 mmol) (61%)
[0715] MS (ESI, m/z) 476 (M-H).sup.-
[0716] .sup.1H-NMR (CDCl3): 1.80 (2H, quint), 2.51 (2H, t), 2.72
(3H, s), 3.26 (3H, s), 3.37 (2H, q), 6.52 (1H, t), 7.09-7.12 (2H,
m), 7.16-7.21 (1H, m), 7.25-7.30 (2H, m), 7.46 (1H, t), 7.78 (1H,
d).
[0717] 2) Synthesis of Synthesis of
2-ethyl-4-(3,5-dichlorophenyl)-6-methy-
l-N-(3-phenylpropyl)-5-pyrimidinecarboxamide:
[0718] 100 mg (0.209 mmol) of
4-(3,5-dichlorophenyl)-6-methyl-2-(methylsul-
fonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in
3 ml of THF. 0.314 ml (13% THF solution, 1 mol/l) of ethylmagnesium
bromide was added at 0.degree. C. and stirred at the same
temperature for 1 hour. 10% hydrochloric acid was added at the same
temperature and stirred for 10 minutes. After the reaction mixture
was diluted with ethyl acetate, the organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 1/1) to obtain the title compound.
[0719] Yield: 18.2 mg (0.0425 mmol) (20%)
[0720] MS (ESI, m/z) 428 (M+H).sup.+ 426 (M-H).sup.-
[0721] .sup.1H-NMR (CDCl3): 1.38 (3H, t), 1.75 (2H, quint), 2.49
(2H, t), 2.59 (3H, s), 2.99 (2H, q), 3.34 (2H, q), 5.48 (1H, br t),
7.07-7.09 (2H, m), 7.15-7.20 (1H, m), 7.24-7.29 (2H, m), 7.40-7.41
(1H, m), 7.69-7.70 (2H, m).
EXAMPLE 104
[0722] Synthesis of
4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
n-propyl)-5-pyrimidinecarboxamide:
[0723] 100 mg (0.209 mmol) of
4-(3,5-dichlorophenyl)-6-methyl-2-methylsulf-
onyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 3
ml of THF. 0.349 ml (0.90 mol/l, THF solution) of n-propyl
magnesium bromide was added at 0.degree. C. and stirred at the same
temperature for 1 hour. 10% hydrochloric acid was added at the same
temperature and stirred for 10 minutes. After the reaction mixture
was diluted with ethyl acetate, the organic layer was washed with
saturated aqueous sodium chloride solution and dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 1/1) to obtain the title compound.
[0724] Yield: 27.3 mg (0.0617 mmol) (30%)
[0725] MS (ESI, m/z) 442 (M+H).sup.+ 440 (M-H).sup.-
[0726] .sup.1H-NMR (CDCl3): 1.02 (3H, t), 1.75 (2H, quint), 1.87
(2H, sext), 2.49 (2H, t), 2.58 (3H, s), 2.94 (2H, t), 3.34 (2H, q),
5.49 (1H, br t), 7.07-7.10 (2H, m), 7.09-7.20 (1H, in), 7.24-7.29
(3H, m), 7.41 (1H, t), 7.69 (2H, d).
EXAMPLE 105
[0727] Synthesis of
2-butyl-4-(3,5-dichlorophenyl)-6-methyl-N-(3-phenylpro-
pyl)-2-(n-propyl)-5-pyrimidinecarboxamide:
[0728] 100 mg (0.209 mmol) of
4-(3,5-dichlorophenyl)-6-methyl-2-(methylsul-
fonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in
3 ml of THF. 0.349 ml (0.90 mol/l, THF solution) of n-butyl
magnesium chloride was added at 0.degree. C. and stirred at the
same temperature for 1 hour. 10% hydrochloric acid was added at the
same temperature and stirred for 10 minutes. After the reaction
mixture was diluted with ethyl acetate, the organic layer was
washed with saturated aqueous sodium chloride solution and dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by the silica gel
chromatography hexane/ethyl acetate=10/1 to 1/1) to obtain the
title compound.
[0729] Yield: 15.6 mg (0.0342 mmol) (16%)
[0730] MS (ESI, m/z) 456 (M+H).sup.+ 454 (M-H).sup.-
[0731] .sup.1H-NMR (CDCl3): 0.96 (3H, t), 1.43 (2H, sext),
1.70-1.86 (4H, m), 2.49 (2H, t), 2.58 (3H, s), 2.96 (2H, t), 3.33
(2H, q), 5.48 (1H, br t), 7.07-7.10 (2H, m), 7.15-7.21 (1H, m),
7.24-7.30 (2H, m), 7.41 (1H, t), 7.69 (2H, d).
EXAMPLE 106
[0732] Synthesis of
4-(2,4-dimethylphenyl)-6-methyl-2-(methylsulfinyl)-N-(-
3-phenylpropyl)-5-pyrimidinecarboxamide:
[0733] The title compound was obtained by using 210 mg (0.52 mmol)
of
4-(2,4-dimethylphenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrim-
idinecarboxamide and 179 mg (1.04 mmol) of mCPBA
(m-chloroperbenzoic acid), in the same manner as that of Example
103 1).
[0734] Yield: 52 mg (0.12 mmol) (23%)
[0735] MS (ESI, m/z) 422 (M+H).sup.+
[0736] .sup.1H-NMR (CDCl3): 1.51 (2H, quint), 2.25-2.36 (8H, m),
2.74 (3H, s), 3.24 (2H, q), 3.31 (3H, s), 5.62 (1H, br t),
7.01-7.09 (4H, m), 7.15-7.29 (4H, m).
EXAMPLE 107
[0737] Synthesis of
4-(2,4-dimethylphenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
n-propyl)-5-pyrimidinecarboxamide:
[0738] The title compound was obtained by using 210 mg (0.518 mmol)
of
4-(2,4-dimethylphenyl)-6-methyl-2-(methylthio)-N-(3-phenylpropyl)-5-pyrim-
idinecarboxamide, 179 mg (1.04 mmol) of mCPBA and 0.49 ml (0.439
mmol) of n-propyl magnesium bromide (0.90 mol/l, THF solution), in
the same manner as that of Example 103.
[0739] Yield: 49.6 mg (0.124 mmol) (23%)
[0740] MS (ESI, m/z) 402 (M+H).sup.+
[0741] .sup.1H-NMR (CDCl3): 0.99 (3H, t), 1.44 (2H, quint),
1.78-1.91 (2H, m), 2.22 (6H, s), 2.29 (2H, t), 2.61 (3H, s),
2.90-2.95 (2H, m), 2.17 (2H, q), 5.22 (1H, br t), 7.00-7.05 (4H,
m), 7.14-7.29 (4H, m).
EXAMPLE 108
[0742] Synthesis of
4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-N-(3-phe-
nylpropyl)-5-pyrimidinecarboxamide:
[0743] 1) Synthesis of 3-(3,5-dichlorophenyl)-2-propionyl-acrylic
methylester:
[0744] 1.00 g (7.68 mmol) of 3-oxovaleric acid methylester and 1.34
g (7.68 mmol) of 3,5-dichlorobenzaldehyde were dissolved in 20 ml
of 2-propanol. 65.4 mg (0.768 mmol) of piperidine and 46.1 mg
(0.768 mmol) of acetic acid were added and stirred at room
temperature for one day. After the solvent was evaporated under
reduced pressure, ethyl acetate was added thereto. The reaction
mixture was washed with 1 N hydrochloric acid and then with
saturated aqueous sodium hydrogencarbonate solution. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain
the title compound.
[0745] Yield: 1.77 g (23.4 mmol) (83%)
[0746] MS (ESI, m/z) 304 (M+NH4).sup.+
[0747] .sup.1H-NMR (CDCl3): 1.10-1.18 (3H, m), 2.57 and 2.74 (total
2H, ratio 1:1, q, q, respectively), 3.84 (3H, d), 7.21-7.23 (1H,
m), 7.28-7.29 (1H, m), 7.37-7.40 (1H, m), 7.46 and 7.55 (total 1H,
ratio 1:1, s, s, respectively).
[0748] 2) Synthesis of
4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-1,4-d-
ihydropyrimidine-5-carboxylic acid methylester:
[0749] 1.00 g (3.48 mmol) of
3-(3,5-dichlorophenyl)-2-propionyl-acrylic methylester was
dissolved in 10 ml of DMF. 776 mg (2.79 mmol) of
methylisothiourea-sulfate and 428 mg (5.22 mmol) of sodium acetate
were added at room temperature and stirred at the same temperature
for 2 days. After DMF was evaporated under reduced pressure, the
reaction mixture was diluted with ethyl acetate. The organic layer
was washed with saturated aqueous sodium chloride solution and
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was dissolved in toluene and
catalytic amount of silica gel was added and stirred at 100.degree.
C. for one day. After filtering silica gel, the filtrate was
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=10/1 to 2/1) to
obtain the title compound.
[0750] Yield: 475 mg (1.32 mmol) (38%)
[0751] MS (ESI, m/z) 359 (M+H).sup.+ 357 M-H).sup.-
[0752] .sup.1H-NMR (CDCl3): 1.20 (3H, t), 2.41 (3H, s), 2.61-2.88
(2H, m), 3.66 (3H, s), 5.65 and 6.36 (total 1H, ratio 1:1, br s, br
s, respectively), 7.17-7.21 (3H, m).
[0753] 3) Synthesis of
4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-pyrim-
idine-5-carboxylic acid methylester:
[0754] 475 mg (1.32 mmol) of
4-(3,5-dichlorophenyl)-2-(methylthio)-1,4-dih-
ydropyrimidine-5-carboxylic acid methylester was dissolved in 30 ml
of chloroform. 1.72 g (19.8 mmol) of manganese dioxide was added
and stirred at 80 .degree. C. for 3 hours. After filtration of
insoluble matters, the filtrate was concentrated under reduced
pressure. The residue was purified by the silica gel chromatography
(hexane/ethyl acetate=10/1 to 1/1) to obtain the title
compound.
[0755] Yield: 369 mg (1.03 mmol) (78%)
[0756] MS (ESI, m/z) 357 (M+1H)+
[0757] .sup.1H-NMR (CDCl3): 1.32 (3H, t), 2.62 (3H, s), 2.83 (2H,
q), 3.75 (3H, s), 7.44-7.46 (1H, m), 7.50-7.51 (2H, m).
[0758] 4) Synthesis of
4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-pyrim-
idine-5-carboxylic acid:
[0759] 274 mg (0.768 mmol) of
4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio-
)-pyrimidine-5-carboxylic acid methylester was dissolved in 5 ml of
THF and 5 ml of water. 33.7 mg (0.922 mmol) of lithium hydroxide
monohydrate was added and stirred at 80.degree. C. for 12 hours. 10
ml of water was added thereto and the organic layer was batched
off. The obtained aqueous layer was diluted with ethyl acetate and
washed with 5ml of 3 N hydrochloric acid and then with 5ml of
saturated aqueous sodium chloride solution. The organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure to obtain the title compound.
[0760] Yield: 183 mg (0.533 mmol) (70%)
[0761] MS (ESI, m/z) 343 (M+H).sup.+ 341 (M-H).sup.-
[0762] .sup.1H-NMR (CDCl3): 1.32 (3H, t), 2.61 (3H, s), 2.87 (2H,
q), 7.42-7.44 (1H, m), 7.58-7.59 (2H, m).
[0763] 5) Synthesis of
4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-N-(3--
phenylpropyl)-5-pyrimidinecarboxamide:
[0764] 183 mg (0.533 mmol) of
4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio-
)-pyrimidine-5-carboxylic acid and 86.5 mg (0.640 mmol) of
phenylpropylamine were dissolved in 10 ml of dichloromethane. 153
mg (0.800 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide
hydrochloride (hereinafter referred to as WSC hydrochloride) was
added under cooling with ice and stirred at room temperature
overnight. After concentration under reduced pressure, the reaction
mixture was diluted with ethyl acetate. The reaction mixture was
washed with 1 N hydrochloric acid, saturated aqueous sodium
hydrogencarbonate solution and saturated aqueous sodium chloride
solution. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 1/1) to obtain the title compound.
[0765] Yield: 130 mg (0.283 mmol) (53%)
[0766] MS (ESI, m/z) 460 (M+H).sup.+ 458 (M-H).sup.-
[0767] .sup.1H-NMR (CDCl3): 1.32 (3H, t), 1.72 (2H, quint), 2.47
(2H, t), 2.61 (3H, s), 2.82 (2H, q), 3.31 (2H, q), 5.44 (1H, br t),
7.06-7.08 (2H, m), 7.16-7.20 (1H, m), 7.24-7.29 (2H, m), 7.40-7.41
(1H, m), 7.68-7.69 (2H, m).
EXAMPLE 109
[0768] Synthesis of
4-(2,4-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0769] The title compound was obtained by using 200 mg (0.532 mmol)
of 2-acetyl-3-(2,4-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
111 mg (0.398 mmol) of methylisothiourea-sulfate and 87.0 mg (1.06
mmol) of sodium acetate, in the same manner as that of Example
1.
[0770] Yield: 69.0 mg (0.155 mmol) (28%)
[0771] MS (ESI, m/z) 446 (M+H).sup.+
[0772] .sup.1H-NMR (CDCl3): 1.53 (2H, quint), 2.41 (2H, t), 2.55
(3H, s), 2.56 (3H, s), 3.19 (2H, q), 5.56 (1H, br t), 7.05-7.08
(2H, m), 7.16-7.22 (1H, m), 7.25-7.31 (4H, m), 7.46 (1H, t).
EXAMPLE 110
[0773] Synthesis of
4-(2,6-dichlorophenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0774] The title compound was obtained by using 170 mg (0.452 mmol)
of 2-acetyl-3-(2,6-dichlorophenyl)-N-(3-phenylpropyl) acrylamide,
94.0 mg (0.338 mmol) of methylisothiourea-sulfate and 74.2 mg
(0.904 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0775] Yield: 35.6 mg (0.081 mmol) (18%)
[0776] MS (ESI, m/z) 446 (M+H).sup.+
[0777] .sup.1H-NMR (CDCl3): 1.51 (2H, quint), 2.37-2.43 (2H, m),
2.57 (3H, s), 2.59 (3H, s), 3.21 (2H, q), 5.79 (1H, br t),
7.05-7.08 (2H, m), 7.16-7.37 (6H, m).
EXAMPLE 111
[0778] Synthesis of
4-(2,4-dimethylphenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enyl-2-propen-1-yl)-5-pyrimidinecarboxamide:
[0779] The title compound was obtained by using 453 mg (1.36 mmol)
of 2-acetyl-3-(2,4-dimethylphenyl)-N-(3-phenyl-2-propen-1-yl)
acrylamide, 284 mg (1.02 mmol) of methylisothiourea-sulfate and 223
mg (2.72 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0780] Yield: 110 mg (0.273 mmol) (19%)
[0781] MS (ESI, m/z) 404 (M+H).sup.+
[0782] .sup.1H-NMR (CDCl3): 2.24 (3H, s), 2.25 (3H, s), 2.55 (3H,
s), 2.60 (3H, s), 3.90 (2H, td), 5.24 (1H, br t), 5.60 (1H, dt),
6.22 (1H, d), 6.99-7.05 (2H, m), 7.16-7.34 (6H, m).
EXAMPLE 112
[0783] Synthesis of
4-(2,4-dichlorophenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
n-propyl)-5-pyrimidinecarboxamide:
[0784] The title compound was obtained by using 200 mg (0.532 mmol)
of .sup.2-acetyl-3-(2,4-dichlorophenyl)-N-(3-phenylpropyl)
acrylamide, 160 mg (0.797 mmol) of
n-propyl-carbamidine-trifluoroacetate and 87.3 mg (1.06 mmol) of
sodium acetate, in the same manner as that of Example 61.
[0785] Yield: 87.9 mg (0.199 mmol) (37%)
[0786] MS (ESI, m/z) 442 (M+H).sup.+ 440 (M-H).sup.-
[0787] 1H-NMR (CDCl3): 0.99 (3H, t), 1.55 (2H, quint), 1.84 (2H,
sext), 2.42 (2H, t), 2.60 (3H, s), 2.93 (2H, t), 3.21 (2H, q), 5.62
(1H, br t), 7.05-7.07 (2H, m), 7.16-7.21 (1H, m), 7.25-7.34 (4H,
m), 7.46-7.47 (1H, m).
EXAMPLE 113
[0788] Synthesis of
4-(2,5-dimethylphenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0789] The title compound was obtained by using 284 mg (0.847 mmol)
of 2-acetyl-3-(2,5-dimethylphenyl)-N-(3-phenylpropyl) acrylamide,
189 mg (0.678 mmol) of methylisothiourea-sulfate and 139 mg (1.69
mmol) of sodium acetate, in the same manner as that of Example
61.
[0790] Yield 94.8 mg (0.234 mmol) (28%)
[0791] MS (ESI, m/z) 406 (M+H).sup.+ 404 (M-H).sup.-
[0792] .sup.1H-NMR (CDCl3): 1.40 (2H, quint), 2.23-2.31 (8H, m),
2.56 (6H, d), 3.12 (2H, q), 5.18 (1H, br t), 7.00-7.07 (4H, m),
7.13-7.20 (2H, m), 7.23-7.28 (2H, m).
EXAMPLE 114
[0793] Synthesis of
4-(2,5-dimethylphenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
n-propyl)-5-pyrimidinecarboxamide:
[0794] The title compound was obtained by using 284 mg (0.847 mmol)
of 2-acetyl-3-(2,5-dimethylphenyl)-N-(3-phenylpropyl) acrylamide,
254 mg (1.27 mmol) of n-propyl-carbamidine-trifluoroacetate and 139
mg (1.69 mmol) of sodium acetate, in the same manner as that of
Example 61.
[0795] Yield: 155 mg (0.386 mmol) (46%)
[0796] MS (ESI, m/z) 402 (M+H).sup.+ 400 (M-H).sup.-
[0797] .sup.1H-NMR (CDCl3): 0.99 (3H, t), 1.42 (2H, quint), 1.85
(2H, sext), 2.19 (3H, s), 2.24 (3H, s), 2.29 (1H, t), 2.61 (3H, s),
2.93 (2H, t), 3.14 (2H, q), 5.21 (1H, br t), 7.01-7.06 (4H, m),
7.12-7.28 (4H, m).
EXAMPLE 115
[0798] Synthesis of
4-(4-chlorophenyl)-6-methyl-2-(methylthio)-N-(3-phenyl-
propyl)-5-pyrimidinecarboxamide:
[0799] The title compound was obtained by using 210 mg (0.614 mmol)
of 2-acetyl-3-(4-chlorophenyl)-N-(3-phenylpropyl) acrylamide, 128
mg (0.460 mmol) of methylisothiourea-sulfate and 101 mg (1.23 mmol)
of sodium acetate, in the same manner as that of Example 1.
[0800] Yield: 121 mg (0.294 mmol) (48%)
[0801] MS (ESI, m/z) 412 (M+H).sup.+
[0802] .sup.1H-NMR (CDCl3): 1.69 (2H, quint), 2.45 (2H, t), 2.54
(3H, s), 2.60 (3H, s), 3.28 (2H, q), 5.41 (1H, br t), 7.04-7.06
(2H, m), 7.15-7.21 (1H, m), 7.24-7.30 (2H, m), 7.39-7.44 (2H, m),
7.75-7.80 (2H, m).
EXAMPLE 116
[0803] Synthesis of
4-(chorophenyl)-6-methyl-N-(3-phenylpropyl)-2-n-propyl-
-5-pyrimidinecarboxamide:
[0804] The title compound was obtained by using 210 mg (0.614 mmol)
of 2-acetyl-3-(4-chlorophenyl)-N-(3-phenylpropyl) acrylamide, 184
mg (0.921 mmol) of n-propyl-amidine-trifluoroacetate and 101 mg
(1.23 mmol) of sodium acetate, in the same manner as that of
Example 1.
[0805] Yield: 20.3 mg (0.0498 mmol) (8.0%)
[0806] MS (ESI, m/z) 408 (M+H).sup.+
[0807] .sup.1H-NMR (CDCl3): 1.02 (3H, t), 1.69 (2H, quint), 1.87
(2H, sext), 2.45 (2H, t), 2.58 (3H, s), 2.91-2.96 (2H, m), 3.30
(2H, q), 5.41 (1H, br t), 7.04-7.07 (2H, m), 7.18-7.20 (1H, m),
7.24-7.30 (2H, m), 7.40-7.44 (2H, m), 7.74-7.78 (2H, m).
EXAMPLE 117
[0808] Synthesis of
4-(2,6-dimethylphenyl)-6-methyl-2-(methylthio)-N-(3-ph-
enylpropyl)-5-pyrimidinecarboxamide:
[0809] The title compound was obtained by using 267 mg (0.794 mmol)
of 2-acetyl-3-(2,6-dimethylphenyl)-N-(3-phenylpropyl) acrylamide,
177 mg (0.635 mmol) of methylisothiourea-sulfate and 130 mg (1.59
mmol) of sodium acetate, in the same manner as that of Example
61.
[0810] Yield: 42.4 mg (0.105 mmol) (13%)
[0811] MS (ESI, m/z) 406 (M+H).sup.+ 404 (M-H).sup.-
[0812] .sup.1H-NMR (CDCl3): 1.38 (2H, quint), 2.10 (6H, s), 2.32
(2H, t), 2.56 (3H, s), 2.59 (3H, s), 3.11 (2H, q), 5.16 (1H, br t),
7.05 (4H, t), 7.13-7.29 (4H, m).
EXAMPLE 118
[0813] Synthesis of
4-(2,6-dimethylphenyl)-6-methyl-N-(3-phenylpropyl)-2-(-
n-propyl)-5-pyrimidinecarboxamide:
[0814] The title compound was obtained by using 267 mg (0.794 mmol)
of 2-acetyl-3-(2,6-dimethylphenyl)-N-(3-phenylpropyl) acrylamide,
238 mg (1.19 mmol) of n-propyl-carbamidine-trifluoroacetate and 130
mg (1.59 mmol) of sodium acetate, in the same manner as that of
Example 61.
[0815] Yield: 24.7 mg (0.0615 mmol) (7.8%)
[0816] MS (ESI, m/z) 402 (M+H).sup.+ 400 (M-H).sup.-
[0817] .sup.1H-NMR (CDCl3): 0.95-1.05 (3H, m), 1.36-1.56 (2H, m),
1.79-1.96 (2H, m), 2.07 (6H, s), 2.30-2.39 (5H, m), 2.63 (3H, s),
2.91-3.00 (2H, m), 3.10-3.20 (2H, m), 5.22 (1H, br), 7.03-7.29 (8H,
m).
EXAMPLE 119
[0818] Synthesis of 4-(3-chlorophenyl)-5-(3,3-diphenylpropyl)
carbamoyl-2,6-dimethylcarboxylic acid:
[0819] 1) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid mono (2-cyanoethyl) ester:
[0820] 3.53 g (22.9 mmol) of 3-aminocrotonate 2-cyanoethyl, 4.40 g
(22.9 mmol) of acetoacetic acid benzyl ester and 2.60 ml (23.0
mmol) of 3-chlorobenzaldehyde were heated and stirred at 80.degree.
C. for 3 days in 100 ml of 2-propanol. 2-propanol was evaporated
under reduced pressure to obtain
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbo-
xylic acid 3-(2-cyanoethyl) ester 5-benzyl ester. 100 ml of ethyl
acetate and 10% palladium carbon were added thereto and stirred at
room temperature in hydrogen atmosphere under normal pressure for 7
days. After filtering the reaction mixture, the filtrate was
evaporated under reduced pressure. The residue was washed with
chloroform to obtain the title compound.
[0821] Yield: 4.82 g (13.4 mmol) (58%)
[0822] MS (ESI, m/z) 359 (M-H).sup.-
[0823] .sup.1H-NMR (DMSO-d6): 2.27 (3H, s), 2.29 (3H, s), 2.79-2.86
(2H, m), 4.15 (2H, t), 4.87 (1H, s), 7.10-7.28 (5H, m), 8.90 (1H,
s).
[0824] 2) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(3,3-diphenylprop-
ylcarbamoyl)-1,4-dihydropyridine-3-dicarboxylic acid 2-cyanoethyl
ester:
[0825] 219 mg (0.610 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydrop-
yridine-3,5-dicarboxylic acid mono (2-cyanoethyl) ester, 138 mg
(0.720 mmol) of WSC hydrochloride, 201 mg (0.950 mmol) of
3,3-diphenylpropylamine and 20.0 mg (0.160 mmol) of
4-dimethylaminopyridine were stirred at room temperature overnight
in 10 ml of dichloromethane. 2 N hydrochloric acid was added and
the reaction mixture was extracted with dichloromethane. The
organic layer was dried over anhydrous sodium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=1/1) to obtain
the title compound.
[0826] Yield: 280 mg (0.510 mmol) (83%)
[0827] MS (ESI, m/z) 554 (M+H).sup.+
[0828] .sup.1H-NMR (CDCl3): 2.05-2.23 (2H, m), 2.21 (3H, s), 2.32
(3H, s), 2.64 (2H, t), 3.06-3.22 (2H, m), 3.72 (1H, t), 4.20-4.35
(2H, m), 4.73 (1H, s), 5.31 (1H, t), 5.58 91H, s), 7.09-7.30 (14H,
m).
[0829] 3) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(3,3-diphenylprop-
ylcarbamoyl)-1,4-dihydropyridine-3-carboxylic acid:
[0830] 275 mg (0.500 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-5-(3,3-diphe-
nylpropylcarbamoyl)-1,4-dihydropyridine-3-carboxylic acid
2-cyanoethyl ester was dissolved in 10 ml of methanol. 1 ml of 1 N
aqueous sodium hydroxide solution was added and stirred at room
temperature for 7.5 hours. After adding 2 N hydrochloric acid,
methanol was evaporated under reduced pressure. Water was added to
the residue, and precipitates thus formed were taken by the
filtration, then washed with water and hexane/ethyl acetate (3/1)
and dried under reduced pressure to obtain the title compound.
[0831] Yield: 158 mg (0.320 mmol) (63%)
[0832] MS (ESI, m/z) 499 (M-H).sup.-
[0833] .sup.1H-NMR (DMSO-d6): 2.01 (3H, s), 2.03-2.17 (2H, s) 2.23
(3H, s), 2.82-3.03 (2H, m), 3.84 (1H, t), 4.82 (1H, s), 7.08-7.31
(14H, m), 7.56 (1H, t), 8.26 (1H, s).
[0834] 4) Synthesis of 4-(3-chlorophenyl)-5-(3,3-diphenylpropyl)
carbamoyl-2,6-dimethylcarboxylic acid:
[0835] 2 ml of acetone was added to 57.3 mg (0.110 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-5-(3,3-diphenylpropylcarbamoyl)-1,4-dihyd-
ropyridine-3-carboxylic acid. 178 mg (0.320 mmol) of cerium
ammonium nitrate suspended in 1 ml of water was added and stirred
at room temperature for 2.5 hours. After adding water and
extracting with ethyl acetate, the organic layer was dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure to obtain the title compound.
[0836] Yield: 50.2 mg (0.100 mmol) (88%)
[0837] MS (ESI, m/z) 497 (M-H).sup.-
[0838] .sup.1H-NMR (DMSO-d6): 1.77 (2H, q), 2.47 (3H, s), 2.54 (3H,
s), 2.86 (2H, q), 3.74 (1H, t), 7.13-7.42 (14H, m), 8.34 (1H, br
d).
EXAMPLE 120
[0839] Synthesis of
4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxyl- ic acid
mono (3,3-diphenylpropyl) ester:
[0840] 1) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester
5-(3,3-diphenylpropane-1-yl) ester
[0841] 747 mg (2.52 mmol) of acetoacetic acid, 389 mg (2.52 mmol)
of 3-aminocrotonate 2-cyanoethyl ester and 0.285 ml (2.52 mmol) of
3-chlorobenzaldehyde were heated and stirred at 80.degree. C. for
two nights in 20 ml of 2-propanol. After 2-propanol was evaporated
under reduced pressure, the residue was purified by the silica gel
chromatography (hexane/ethyl acetate=2/1) to obtain the title
compound.
[0842] Yield: 814 mg (1.47 mmol) (58%)
[0843] MS (ESI, m/z) 553 (M-H).sup.-
[0844] 1H-NMR (CDCl3): 2.28-2.42 (2H, m), 2.35 (6H, s), 2.64 (2H,
t), 3.91 (1H, t), 3.95-4.02 (2H, m), 4.22-4.39 (2H, m), 5.00 (1H,
s), 5.73 (1H, s), 7.08-7.30 (14H, m)
[0845] 2) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester
[0846] 808 mg (1.46 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropy-
ridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester
5-(3,3-diphenylpropyl) ester was dissolved in 15 ml of methanol. 3
ml of 1 N aqueous sodium hydroxide solution was added and stirred
at room temperature for 2 hours. After adding 2 N hydrochloric
acid, methanol was evaporated under reduced pressure. Water was
added to the residue, and solid matters were taken by the
filtration, then washed with water and hexane/ethyl acetate (3/1)
and dried under reduced pressure to obtain the title compound.
[0847] Yield: 398 mg (0.790 mmol) (54%)
[0848] MS (ESI, m/z) 500 (M-H).sup.-
[0849] 1H-NMR (DMSO-d6): 2.24-2.34 (2H, m), 2.24 (3H, s), 2.29 (3H,
s), 3.81 (2H, t), 3.87 (1H, t), 4.95 (1H, s), 7.09-7.33 (14H, m),
8.85 (1H, s)
[0850] 3) Synthesis of
4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarbo- xylic acid
mono (3,3-diphenylpropyl) ester
[0851] 2 ml of acetone was added to 50.7 mg (0.100 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic
acid mono (3,3-diphenylpropyl) ester. 130 mg (0.240 mmol) of cerium
ammonium nitrate suspended in 1 ml of water was added and stirred
at room temperature for 10 minutes. After adding water and
extracting with ethyl acetate, the organic layer was dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure to obtain the title compound.
[0852] Yield: 398 mg (0.790 mmol (54%)
[0853] MS (ESI, m/z) 498 (M-H).sup.-
[0854] .sup.1H-NMR (DMSO-d6): 2.01 (2H, q), 2.48 (3H, s), 2.54 (3H,
s), 3.78-3.88 (1H, t), 7.14-7.50 (14H, m).
EXAMPLE 121
[0855] Synthesis of 6-(2-aminoethoxy)
methyl-4-(3-chlorophenyl)-5-(3,3-dip-
henylpropylcarbamoyl)-2-methylpyridine-3-carboxylic acid:
[0856] 1) Synthesis of 4-(2-chloroethoxy) acetoacetic acid benzyl
ester:
[0857] 4.00 g (21.0 mmol) of acetoacetic acid benzyl ester was
dissolved in 40 ml of ether. 1.1 ml (21.0 mmol) of bromine was
dropped at 0.degree. C. After stirring at 0.degree. C. for 30
minutes and then at room temperature for 5 hours, about 4 g of ice
and sodium carbonate were added so that pH showed 7 or more. The
organic layer extracted with ether was washed with water and
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, concentrated and dried in vacuo to obtain
4-bromoacetoacetic acid benzyl ester. 1.68 g (24.0 mmol) of sodium
hydride (60% oily substance) was susptended in 20 ml of THF and
11.7 g (21.0 mmol) of 2-chloroethanol was added at -40.degree. C.
4-bromoacetoacetic acid benzyl ester was dropped at -40.degree. C.,
gradually heated and stirred at room temperature for 16 hours.
After adding 1 N hydrochloric acid and extracting with ethyl
acetate, the obtained mixture was washed with water and saturated
aqueous sodium chloride solution. The mixture was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by the silica gel chromatography
(hexane/ethyl acetate=7/3) to obtain the title compound.
[0858] Yield: 3.75 mg (14.0 mmol) (67%)
[0859] 1H-NMR (CDCl3): 3.59 (2H, t), 3.59 (2H, s), 3.72 (2H, t),
4.18 (2H, s), 5.18 (2H, s), 7.35-7.38 (5H, m).
[0860] 2) Synthesis of 2-(2-chloroethoxy)
methyl-4-(3-chlorophenyl)-6-meth-
yl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-benzyl ester
5-(2-cyanoethyl) ester:
[0861] 500 mg (1.90 mmol) of 4-(2-chloroethoxy) acetoacetic acid
benzyl ester, 260 mg (1.90 mmol) of 3-chlorobenzaldehyde, acetic
acid and piperidine were heated and stirred at room temperature for
24 hours in 3 ml of 2-propanol. 280 mg (1.90 mmol) of
3-aminocrotonate 2-cyanoethyl ester was added and further heated
and stirred at 50.degree. C. for 48 hours. 2-propanol was
evaporated under reduced pressure. The residue was purified by the
silica gel chromatography (hexane/ethyl acetate=1/1) to obtain the
title compound.
[0862] Yield: 340 mg (0.640 mmol) (35%)
[0863] MS (ESI, m/z) 531 (M+H).sup.+
[0864] .sup.1H-NMR (CDCl3): 2.39 (3H, s), 2.59 (2H, t), 3.73 (2H,
t), 3.79 (2H, m), 4.22 (2H, m), 4.75 (1H, d), 4.82 (1H, d), 4.98
(1H, s), 5.00 (1H, d), 5.13 (1H, d), 7.11-7.30 (10H, m).
[0865] 3) Synthesis of 2-(2-chloroethoxy)
methyl-4-(3-chlorophenyl)-6-meth-
yl-1,4-dihydropyridine-3,5-dicarboxylic acid 5-(2-cyanoethyl)
ester:
[0866] 5 ml of ethyl acetate and 10% palladium carbon were added to
340 mg (0.640 mmol) of 2-(2-chloroethoxy)
methyl-4-(3-chlorophenyl)-6-methyl-1,4-
-dihydropyridine-3,5-dicarboxylic acid 3-benzyl ester
5-(2-cyanoethyl) ester. The obtained solution was stirred at room
temperature in hydrogen atmosphere under normal pressure for 8
hours. After filtering the reaction mixture, the filtrate was
evaporated under reduced pressure to obtain the title compound.
[0867] Yield: 250 mg (0.560 mmol) (87%)
[0868] MS (ESI, m/z) 437 (M-H).sup.-
[0869] .sup.1H-NMR (CDCl3): 2.41 (3H, s), 2.63 (2H, t), 3.74 (2H,
m), 3.86 (2H, m), 4.25 (2H, m), 4.75 (1H, d), 4.81 (1H, d), 4.95
(1H, s), 7.13-7.26 (4H, m), 7.47 (1H, s).
[0870] 4) Synthesis of 2-(2-chloroethoxy)
methyl-4-(3-chlorophenyl-5-(3,3--
diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic
acid (2-cyanoethyl) ester:
[0871] 250 mg (0.560 mmol) of 2-(2-chloroethoxy)
methyl-4-(3-chlorophenyl)-
-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid
5-(2-cyanoethyl) ester, 110 mg (0.570 mmol) of WSC hydrochloride
and 120 mg (0.570 mmol) of 3,3-diphenylpropylamine were stirred at
room temperature for 15 hours in 4 ml of dichloromethane. After
evaporating dichloromethane under reduced pressure, 0.1 N
hydrochloric acid was added and the reaction mixture was extracted
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography (hexane/ethyl
acetate=1/1) to obtain the title compound.
[0872] Yield: 280 mg (0.450 mmol) (80%)
[0873] MS (ESI, m/z) 632 (M+H).sup.+
[0874] .sup.1H-NMR (CDCl3): 2.14 (2H, s), 2.67 (2H, t), 3.10 (2H,
m), 3.72 (2H, m), 3.83 (2H, m), 4.31 (2H, m), 4.73 (1H, s), 4.82
(2H, s), 5.56 (1H, t), 7.11-7.26 (15H, m).
[0875] 5) Synthesis of 6-(2-azidoethoxy)
methyl-4-(3-chlorophenyl)-5-(3,3--
diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic
acid (2-cyanoethyl) ester:
[0876] 270 mg (0.430 mmol) of 6-(2-chloroethoxy)
methyl-4-(3-chlorophenyl)-
-5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic
acid (2-cyanoethyl) ester was dissolved in 3 ml of 2-propanol. 600
mg (0.400 mmol) of sodium iodide was added thereto and stirred at
60.degree. C. for 20 hours. After the solvent was evaporated under
reduced pressure, sodium iodide separated by adding dichloromethane
was taken by filtration. The filtrate was concentrated under
reduced pressure and stirred together with 33.0 mg (0.490 mmol) of
sodium azide at 50.degree. C. for 6 hours in 2 ml of DMF After
adding ethyl acetate, the reaction mixture was washed with water
and saturated aqueous sodium chloride solution. The organic layer
was dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure to obtain the title compound.
[0877] Yield: 250 mg (0.390 mmol) (90%)
[0878] MS (ESI, m/z) 639 (M+H).sup.+
[0879] .sup.1H-NMR (CDCl3): 2.15 (2H, m), 2.34 (3H, s), 2.69 (2H,
t), 3.10 (2H, m), 3.48 (2H, m), 3.66 (1H, t), 3.75 (2H, m), 4.32
(2H, m), 4.73 (1H, s), 4.83 (2H, s), 5.55 (1H, t), 7.09-7.32 (15H,
m).
[0880] 6) Synthesis of 6-(2-azidoethoxy)
methyl-4-(3-chlorophenyl)-5-(3,3--
diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic
acid:
[0881] 250 mg (0.390 mmol) of 6-(2-azidoethoxy)
methyl-4-(3-chlorophenyl)--
5-(3,3-diphenylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic
acid (2-cyanoethyl) ester was dissolved in 2 ml of methanol. 0.70
ml of 1 N aqueous sodium hydroxide solution was added and stirred
at room temperature for 8 hours. After adding 1 N hydrochloric acid
and water, precipitates thus formed were taken by the filtration
and dried under reduced pressure to obtain the title compound.
[0882] Yield: 190 mg (0.320 mmol) (84%)
[0883] MS (ESI, m/z) 584 (M-H).sup.-
[0884] .sup.1H-NMR (CDCl3): 2.15 (2H, m), 2.34 (3H, s), 3.10 (2H,
m), 3.50 (2H, m), 3.66 (1H, t), 3.76 (2H, m), 4.72 (1H, s), 4.87
(2H, s), 5.49 (1H, t), 7.08-7.33 (15H, m).
[0885] 7) Synthesis of 6-(2-aminoethoxy)
methyl-4-(3-chlorophenyl)-5-(3,3--
diphenylpropylcarbamoyl)-2-methylpyridine-3-carboxylic acid:
[0886] 3 ml of ethyl acetate and 10% palladium carbon were added to
0.100 g (0.170 mmol) of 6-(2-azidoethoxy)
methyl-4-(3-chlorophenyl)-5-(3,3-diph-
enylpropylcarbamoyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid
and stirred at room temperature in hydrogen atmosphere under normal
pressure for 40 hours. The reaction mixture was filtered and the
filtrate was evaporated under reduced pressure. The residue thus
obtained by evaporating the solvent was subjected to Reversed-phase
High-performance Liquid Chromatography using octadodecyl group
bounded type silica gel as a filler. Then, the obtained substance
was eluted with the mixed solvent of water and acetonitrile. The
fraction of the object compound was freeze-dried to obtain the
title compound as a by-product material of 6-(2-aminoethoxy)
methyl-4-(3-chlorophenyl)-5-(3,3-diphenylpropylcarbamoy-
l)-2-methyl-1,4-dihydropyridine-3-carboxylic acid.
[0887] Yield: 9.10 mg (0.0160 mmol) (10%)
[0888] MS (ESI, m/z) 556 (M-H).sup.-
[0889] .sup.1H-NMR (CD3OD): 1.80 (2H, q), 2.63 (3H, s), 3.00 (2H,
t), 3.07 (2H, t), 3.65-3.72 (3H, t), 4.66 (2H, s), 7.10-7.30 (14H,
m).
EXAMPLE 122
[0890] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(piperazine-1-carbon-
yl)nicotinic acid (3,3-diphenylpropyl) ester:
[0891] 1) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester
5-(3,3-diphenylpropyl) ester:
[0892] 747 mg (2.52 mmol) of acetoacetic acid 3,3-diphenylpropyl
ester, 389 mg (2.52 mmol) of 3-aminocrotonate 2-cyanoethyl ester
and 0.285 ml (2.52 mmol) of 3-chlorobenzaldehyde were heated and
stirred at 80.degree. C. for two nights in 20 ml of 2-propanol.
After 2-propanol was evaporated under reduced pressure, the residue
was purified by the silica gel chromatography (hexane/ethyl
acetate=2/1) to obtain the title compound.
[0893] Yield: 814 mg (1.47 mmol) (58%)
[0894] MS (ESI, m/z) 553 (M-H).sup.-
[0895] .sup.1H-NMR (CDCl3): 2.28-2.42 (2H, m), 2.35 (6H, s), 2.64
(2H, t), 3.91 (1H, t), 3.95-4.02 (2H, m), 4.22-4.39 (2H, m), 5.00
(1H, s), 5.73 (1H, s), 7.08-7.30 (14H, m).
[0896] 2) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester:
[0897] 808 mg (1.46 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropy-
ridine-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester
5-(3,3-diphenylpropyl) ester was dissolved in 15 ml of methanol. 3
ml of 1 N aqueous sodium hydroxide solution was added and stirred
at room temperature for 2 hours. After adding 2 N hydrochloric
acid, methanol was evaporated under reduced pressure. Water was
added thereto and the solid substance was filtered. The obtained
substance was washed with water and then hexane/ethyl acetate (3/1)
and dried under reduced pressure to obtain the title compound.
[0898] Yield: 398 mg (0.790 mmol) (54%)
[0899] MS (ESI, m/z) 500 (M-H).sup.-
[0900] .sup.1H-NMR (DMSO-d6): 2.24-2.34 (2H, m), 2.24 (3H, s), 2.29
(3H, s), 3.81 (2H, t), 3.87 (1H, t), 4.95 (1H, s), 7.09-7.33 (14H,
m), 8.85 (1H, s).
[0901] 3) Synthesis of
4-[4-(3-chlorophenyl)-5-(3,3-diphenylpropoxycarbony-
l)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl]
piperazine-1-carboxylic acid-t-butyl ester:
[0902] 258 mg (0.510 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydrop-
yridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 143
mg (0.770 mmol) of 1-t-butoxycarbonylpiperazine, 117 mg (0.610
mmol) of WSC hydrochloride and 18.0 mg (0.140 mol) of
4-dimethylaminopyridine were stirred at room temperature overnight
in 15 ml of dichloromethane. After adding water and 1 N
hydrochloric acid, the reaction mixture was extracted with
dichloromethane. The organic layer was dried over anhydrous sodium
sulfate and then concentrated under reduced pressure. The residue
was purified by the silica gel chromatography (hexane/ethyl
acetate=1/2) to obtain the title compound.
[0903] Yield: 259 mg (0.390 mol) (77%)
[0904] MS (ESI, m/z) 668 (M-H).sup.-
[0905] .sup.1H-NMR (CDCl3): 1.40-1.48 (2H, m), 1.43 (9H, s), 1.73
(3H, s), 2.10-2.22 (2H, m), 2.38 (3H, s), 2.85-3.15 (4H, m),
3.62-3.92 (5H, m), 4.96 (1H, s), 5.24 (1H, s), 6.92 (2H, d),
7.08-7.29 (12H, m).
[0906] 4) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(piperazine-1-car- bonyl)
nicotinic acid (3,3-diphenylpropyl) ester:
[0907] 233 mg (0.350 mol) of
4-(4-(3-chlorophenyl)-5-(3,3-diphenylpropoxyc-
arbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl)
piperazine-1-carboxylic acid-t-butyl ester was dissolved in 10 ml
of dichloromethane. 5 ml of trifluoroacetate was added and stirred
at room temperature for 2.5 hours. After concentration under
reduced pressure, saturated aqueous sodium hydrogencarbonate
solution was added and the reaction mixture was extracted with
ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate and then concentrated under reduced pressure to obtain the
title compound.
[0908] Yield: 198 mg (0.350 mol) (100%)
[0909] MS (ESI, m/z) 568 (M+H).sup.+
[0910] .sup.1H-NMR (CDCl3): 1.90-2.04 (2H, m), 2.15-2.27 (1H, m),
2.41-2.65 (2H, m), 2.55 (3H, s), 2.58 (3H, s), 2.73-2.88 (2H, m),
2.98-3.08 (1H, m), 3.40-3.55 (2H, m), 3.71 (1H, t), 3.82-4.05 (2H,
m), 7.06-7.29 (14H, m).
EXAMPLE 123
[0911] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-3-(3-phenylpropyl)-5-(-
piperazine-1-carbonyl) nicotinamide:
[0912] 1) Synthesis of
4-[4-(3-chlorophenyl)-5-(2-cyanoethoxycarbonyl)-2,6-
-dimethyl-1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic
acid-t-butyl ester:
[0913] 1.48 g (7.97 mmol) of 1-(t-butoxycarbonyl) piperazine, 0.74
ml (9.59 mmol) of diketene and 0.22 ml (1.58 mmol) of triethylamine
were stirred in 50 ml of toluene at 80.degree. C. for 5 hours.
After ethyl acetate was added, the reaction mixture was washed with
saturated aqueous sodium hydrogencarbonate solution. The organic
layer was dried over anhydrous sodium sulfate and then concentrated
under reduced pressure. The obtained substance was dissolved in 50
ml of benzene. 0.94 ml (8.30 mmol) of 3-chlorobenzaldehyde, 0.08 ml
of piperidine and catalytic amount of p-toluenesulfonic acid were
added and stirred removing water at 120.degree. C. for 7 hours.
After adding ethyl acetate, the reaction mixture was washed with 1
N hydrochloric acid and saturated aqueous sodium hydrogencarbonate
solution. The organic layer was dried over anhydrous sodium sulfate
and then concentrated under reduced pressure. The residue was
purified by the silica gel chromatography (hexane/ethyl
acetate=3/1). The obtained substance was dissolved in 50 ml of
2-propanol. 929 mg (6.03 mmol) of 3-aminocrotonate (2-cyanoethyl)
ester was added and stirred at 80.degree. C. for four nights and
then, after the solvent was removed, stirred at 120.degree. C. for
4 hours. The reaction mixture was purified by the silica gel
chromatography (chloroform/methanol=100/1) to obtain the title
compound.
[0914] Yield: 1.67 g (3.15 mmol) (40%)
[0915] MS (ESI, m/z) 527 (M-H).sup.-
[0916] 1H-NMR (CDCl3): 1.43 (9H, s), 1.76 (3H, s), 2.39 (3H, s),
2.42-2.48 (2H, m), 2.60-4.20 (10H, m ), 4.87 (1H, s), 5.45 (1H,s),
7.10-7.27 (4H, m).
[0917] 2) Synthesis of
4-[5-carboxy-4-(3-chlorophenyl)-2,6-dimethyl-1,4-di-
hydropyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl
ester:
[0918] 6.30 ml (6.30 mmol) of 1 N aqueous sodium hydroxide solution
was added to 1.67 g (3.15 mmol) of
4-[4-(3-chlorophenyl)-5-(2-cyanoethoxycarb-
onyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl]
piperazine-1-carboxylic acid-t-butyl ester in 30 ml of methanol and
stirred at room temperature for 2 hours. 6.30 ml (6.30 mmol) of 1 N
hydrochloric acid was added and concentrated under reduced
pressure. Water was added to the residue and extracted with ethyl
acetate. The organic layer was dried over anhydrous sodium sulfate
and then concentrated under reduced pressure. The obtained solid
substance was filtered, washed with hexane/ethyl acetate (3/1) and
dried under reduced pressure to obtain the title compound.
[0919] Yield: 1.13 g (2.37 mmol) (75%)
[0920] MS (ESI, m/z) 474 (M-H).sup.-
[0921] 1H-NMR (DMSO-d6): 1.37 (9H, s), 1.68 (3H, s), 2.28 (3H, s),
2.80-3.40 (8H, m), 4.64 (1H, s), 7.02-7.05 (2H, m), 7.19-7.32 (2H,
m), 8.28 (1H, s).
[0922] 3) Synthesis of
4-[4-(3-chlorophenyl)-2,6-dimethyl-5-(3-phenylpropy- lcarbamoyl)
pyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl
ester:
[0923] 1.13 g (2.37 mmol) of
4-[5-carboxy-4-(3-chlorophenyl)-2,6-dimethyl--
1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic
acid-t-butyl ester, 0.51 ml (3.59 mmol) of 3-phenylpropylamine, 548
mg (2.86 mmol) of WSC hydrochloride and 21 mg (0.17 mmol) of
4-dimethylaminopyridine were stirred in 10 ml of dichloromethane at
room temperature overnight. After adding 25 ml of water and 25 ml
of 1 N hydrochloric acid, the reaction mixture was extracted with
dichloromethane. The organic layer was washed with saturated
aqueous sodium hydrogencarbonate solution and dried over anhydrous
sodium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography
(chloroform/methanol=300/1) to obtain the title compound.
[0924] Yield: 619 mg (1.05 mmol) (44%)
[0925] MS (ESI, m/z) 589 (M-H).sup.-
[0926] 1H-NMR (CDCl3): 1.35-1.54 (2H, m), 1.41 (9H, s), 2.20-2.39
(2H, m), 2.50 (3H, s), 2.60 (3H, s), 2.70-3.57 (10H, m), 5.43 (1H,
t), 7.01-7.47 (9H, m).
[0927] 4) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-3-(3-phenylpropyl)--
5-(piperazine-1-carbonyl) nicotinamide:
[0928] 619 mg (1.05 mmol) of
4-[4-(3-chlorophenyl)-2,6-dimethyl-5-(3-pheny- lpropylcarbamoyl)
pyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester was
dissolved in 30 ml of dichloromethane. 15 ml of trifluoroacetate
was added and stirred at room temperature for 2 hours. After
concentration under reduced pressure, saturated aqueous sodium
hydrogencarbonate solution was added and the reaction mixture was
extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure. By adding hexane to the residue, the solid substance was
precipitated, filtered and dried under reduced pressure to obtain
the title compound.
[0929] Yield: 377 mg (0.770 mol) (73%)
[0930] MS (ESI, m/z) 489 (M-H).sup.-
[0931] .sup.1H-NMR (CDCl3): 1.37-1.56 (2H, m), 2.21-2.59 (6H, m),
2.50 (3H, s), 2.59 (3H, s), 2.72-2.78 (2H, m), 2.94-3.06 (2H, m),
3.24-3.35 (1H, m), 3.44-3.47 (2H, m), 5.60 (1H, t), 7.02-7.46 (9H,
m).
EXAMPLE 124
[0932] Synthesis of
4-(3,5-dichlorophenyl)-2,6-dimethyl-5-(piperazine-1-ca-
rbonyl)nicotinic acid (3,3-diphenylpropyl) ester:
[0933] 1) Synthesis of
4-[2-acetyl-3-(3,5-dichlorophenyl)-2-propenoyl]
piperazine-1-carboxylic acid-t-butyl ester:
[0934] 2.00 g (10.7 mmol) of 1-(t-butoxycarbonyl), 0.99 ml (12.8
mmol) of diketene and 2.2 ml (16.1 mmol) of trietylamine were
stirred in 50 ml of toluene at 80.degree. C. for 2 hours. After
adding ethyl acetate, the reaction mixture was washed with
saturated aqueous sodium hydrogencarbonate solution. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The obtained substance was
dissolved in 60 ml of benzene. 1.97 g (11.3 mmol) of
3,5-dichlorobenzaldehyde and 0.11 ml (1.13 mmol) of piperidine were
added and stirred removing water at 120.degree. C. for 7 hours.
After adding ethyl acetate, the reaction mixture was washed with 1
N hydrochloric acid and saturated aqueous sodium hydrogencarbonate
solution. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by the silica gel chromatography (hexane/ethyl
acetate=3/1) to obtain the title compound.
[0935] Yield: 1.52 g (3.56 mmol) (33%)
[0936] MS (ESI, m/z)
[0937] .sup.1H-NMR (CDCl3): 1.44 (9H, s), 2.43 (3H, s), 2.75-2.88
(1H, m), 3.07-3.18 (2H, m), 3.25-3.47 (2H, m), 3.55-3.71 (2H, m),
3.78-3.90 (1H, m), 7.35 (1H, s), 7.39-7.40 (3H, m).
[0938] 2) Synthesis of
4-[4-(3,5-dichlorophenyl)-5-(3,3-diphenylpropoxycar-
bonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl]
piperazine-1-carboxylic acid-t-butyl ester:
[0939] 355 mg (1.20 mmol) of acetoacetic acid 3,3-diphenylpropyl
ester and 277 mg (3.59 mmol) of ammonium acetate were stirred in 15
ml of 2-propanol at 55.degree. C. overnight. After evaporating
2-propanol under reduced pressure, ethyl acetate was added and the
reaction mixture was washed with saturated aqueous sodium chloride
solution. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The obtained
substance was dissolved in 15 ml of 2-propanol. 513 mg (1.20 mmol)
of 4-[2-acetyl-3-(3,5-dichlorophenyl)-2-pr- openoyl]
piperazine-1-carboxylic acid-t-butyl ester was added and stirred at
70.degree. C. overnight. After evaporating 2-propanol under reduced
pressure, the residue was purified by the silica gel chromatography
(dichloromethane/methanol=100/1 to 50/1) to obtain the title
compound.
[0940] Yield: 419 mg (0.595 mmol) (49%)
[0941] MS (ESI, m/z) 702 (M-H).sup.-
[0942] 1H-NMR (CDCl3): 1.44 (9H, s), 1.73 (3H, s), 2.13-2.20 (2H,
m), 2.36 (3H, s), 2.70-3.92 (11H, m), 4.96 (1H, br s), 5.54 (1H, br
s), 6.96 (2H, d), 7.09-7.28 (11H, m).
[0943] 3) Synthesis of
4-(3,5-dichlorophenyl)-2,6-dimethyl-5-(piperazinylc- arbonyl)
nicotinic acid (3,3-diphenylpropyl) ester:
[0944] 419 mg (0.595 mmol) of
4-[4-(3,5-dichlorophenyl)-5-(3,3-diphenylpro-
poxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl]
piperazine-1-carboxylic acid-t-butyl ester was dissolved in 15 ml
of dichloromethane. After adding 7 ml of trifluoroacetate under
cooling with ice, the reaction mixture was stirred at room
temperature for 2 hours. After concentration under reduced
pressure, saturated aqueous sodium hydrogencarbonate solution was
added and the reaction mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by the silica gel chromatography (dichloromethane) to obtain the
title compound.
[0945] Yield: 224 mg (0.372 mmol) (63%)
[0946] MS (ESI, m/z) 602 (M+H).sup.+
[0947] .sup.1H-NMR (CDCl3): 2.02-2.10 (3H, m), 2.27-2.35 (1H, m),
2.49-2.55 (4H, m), 2.58 (3H, s), 2.63-2.69 (1H, m), 2.78-2.91 (2H,
m), 3.03-3.10 (1H, m), 3.52 (2H, t), 3.73 (1H, t), 3.90-4.08 (2H,
m), 7.10-7.30 (14H, m).
EXAMPLE 125
[0948] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(4-methylpiperazine--
1-carbonyl)nicotinic acid (3,3-diphenylpropyl) ester:
[0949] 1.564 g (8.16 mmol) of WSC hydrochloride and 0.905 ml (8.16
mmol) of N-methylpiperazine in the ice bath were added to 3.42 g
(6.80 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic
acid mono (3,3-diphenylpropane) ester in 100 ml of dichloromethane
and stirred at room temperature overnight. 30 ml of
trifluoroacetate was added and the reaction mixture was stirred at
room temperature overnight After concentration under reduced
pressure, saturated aqueous sodium hydrogencarbonate solution was
added to basify. After extracting with ethyl acetate, the organic
layer was dried over anhydrous sodium sulfate and then concentrated
under reduced pressure. The residue was purified by the silica gel
chromatography (chloroform/methanol=50/1) to obtain the title
compound.
[0950] Yield: 2.67 g (4.58 mmol) (67%)
[0951] MS (ESI, m/z) 582 (M+H).sup.+
[0952] .sup.1H-NMR (CDCl3): 1.72-2.08 (4H, m), 2.17 (3H, s),
2.12-2.38 (2H, m), 2.55 (3H, s), 2.58 (3H, s), 2.76-3.14 (2H, m),
3.40-3.64 (2H, m), 3.71 (1H, t), 3.83-4.05 (2H, m), 7.05-7.30 (14H,
m).
EXAMPLE 126
[0953] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-[4-(2-hydroxyethyl)
piperazine-1-carbonyl) nicotinic acid (3,3-diphenylpropyl)
ester:
[0954] 118 mg (0.620 mmol) of WSC hydrochloride and 80 mg (0.610
mmol) of 1-(2-hydroxyethyl) piperazine in the ice bath were added
to 252 mg (0.510 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbox-
ylic acid mono (3,3-diphenylpropyl) ester in 8 ml of
dichloromethane and stirred at room temperature overnight.
Saturated aqueous sodium hydrogencarbonate solution was added and
the reaction mixture was extracted with dichloromethane. The
organic layer was dried over anhydrous sodium sulfate and then
concentrated under reduced pressure. The residue was dissolved in 8
ml of dichloromethane. 4 ml of trifluoroacetic acid was added in
the ice bath and stirred at room temperature for 9 hours. The
reaction mixture was concentrated under reduced pressure, followed
by basifying with 1N NaOH aq. After extracting it with ethyl
acetate, The organic layer was dried over anhydrous sodium sulfate
and then concentrated under reduced pressure. The residue was
purified by the basic silica gel chromatography
(chloroform/methanol=1000- /1) to obtain the title compound.
[0955] Yield: 206 g (0.340 mmol) (66%)
[0956] MS (ESI, m/z) 612 (M+H).sup.+
[0957] .sup.1H-NMR (CDCl3): 1.82-2.13 (4H, m), 2.24-2.50 (5H, m),
2.55 (3H, s), 2.59 (3H, s), 2.81-3.15 (2H, m), 3.46-3.60 (4H, m),
3.71 (1H, t), 3.84-4.04 (2H, m), 7.05-7.30 (14H, m).
EXAMPLE 127
[0958] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(pyrrolidine-1-carbo-
nyl)nicotinic acid (3,3-diphenylpropyl) ester:
[0959] 100 mg (0.200 mmol) of
4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-- dicarboxylic acid
mono (3,3-diphenylpropyl) ester, 21.3 mg (0.300 mmol) of
pyrrolidine, 46.0 mg (0.240 mmol) of WSC hydrochloride and 3.00 mg
(0.0250 mmol) of 4-dimethylaminopyridine were stirred in 1.5 ml of
dichloromethane at room temperature overnight. 3.7 mg (0.160 mmol)
of WSC hydrochloride and 1 ml of DMF were added and further stirred
at 60.degree. C. overnight. After adding ethyl acetate and being
washed with water, the organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the thin layer silica gel chromatography
(hexane/ethyl acetate=1/3) to obtain the title compound.
[0960] Yield: 21.6 mg (0.0391 mmol) (20%)
[0961] MS (ESI, m/z) 553 (M+H).sup.+
[0962] .sup.1H-NMR (CDCl3): 1.45-1.84 (4H, m), 1.91-2.06 (2H, m),
2.56 (3H, s), 2.58 (3H, s), 2.74-7.82 (1H, m), 2.92-3.00 (1H, m),
3.10-3.19 (1H, m), 3.45-3.54 (1H, m), 3.71 (1H, t), 3.84-4.02 (2H,
m), 7.06-7.12 (4H, m), 7.13-7.20 (3H, m), 7.22-7.29 (7H, m).
EXAMPLE 128
[0963] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(piperidine-1-carbon-
yl)nicotinic acid (3,3-diphenylpropyl) ester:
[0964] The title compound was obtained by using 100 mg (0.200 mmol)
of 4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylic acid
mono (3,3-diphenylpropyl) ester, 25.5 mg (0.300 mmol) of
piperidine, 76.7 mg (0.400 mmol) of WSC hydrochloride and 3.00 mg
of 4-dimethylaminopyridine, in the same manner as that of Example
127.
[0965] Yield: 50.8 mg (0.0896 mmol) (45%)
[0966] MS (ESI, m/z) 567 (M+H).sup.+
[0967] .sup.1H-NMR (CDCl3): 0.90-1.54 (1H, br s), 1.54-1.39 (2H,
m), 1.39-1.57 (3H, m), 1.86-2.08 (2H, m), 2.55 (3H, s), 2.58 (3H,
s), 2.76-2.83 (1H, m), 2.96-3.04 (1H, m), 3.37-3.52 (2H, m), 3.71
(1H, t), 3.83-4.00 (2H, m), 7.06-7.12 (4H, m), 7.13-7.29 (10H,
m).
EXAMPLE 129
[0968] Synthesis of
5-(azepan-1-carbonyl)-4-(3-chlorophenyl)-2,6-dimethyl-- nicotinic
acid (3,3-diphenylpropyl) ester:
[0969] The title compound was obtained by using 100 mg (0.200 mmol)
of 4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylic acid
mono (3,3-diphenylpropyl) ester, 29.8 mg (0.300 mmol) of
hexamethyleneimine, 76.7 mg (0.400 mmol) of WSC hydrochloride and
3.00 mg of 4-dimethylaminopyridine, in the same manner as that of
Example 127.
[0970] Yield: 51.7 mg (0.0890 mmol) (45%)
[0971] MS (ESI, m/z) 581 (M+H).sup.+
[0972] .sup.1H-NMR (CDCl3): 0.88-1.05 (1H, m), 1.24-1.50 (6H, m),
1.60-1.73 (1H, m), 1.89-2.05 (2H, m), 2.56 (3H, s), 2.58 (3H, s),
2.73-2.81 (1H, m), 3.04 (1H, dt), 3.35-3.43 (2H, m), 3.70 (1H, t),
3.82-4.00 (2H, m), 7.06-7.12 (4H, m), 7.14-7.20 (3H, m), 7.21-7.29
(7H, m).
EXAMPLE 130
[0973] Synthesis of 4-(3-chlorophenyl)-2,6-dimethyl-nicotinic acid
(3,3-diphenylpropyl) ester:
[0974] 447 mg (2.33 mmol) of WSC hydrochloride and 0.254 ml (2.29
mmol) of N-methylpiperazine in the ice bath were added to 952 mg
(1.90 mmol) of
4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5-dicarboxylic acid mono
(3,3-diphenylpropyl) ester in 40 ml of dichloromethane and stirred
at room temperature for 2 nights. Saturated aqueous sodium
hydrogencarbonate solution was added and the reaction mixture was
extracted with dichloromethane. The organic layer was dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure. The residue was purified by the silica gel chromatography
(hexane/ethyl acetate=9/1) to obtain the title compound as a
by-product.
[0975] Yield: 37.0 mg (0.0800 mmol) (4.3%)
[0976] MS (ESI, m/z) 456 (M+H).sup.+
[0977] .sup.1H-NMR (CDCl3): 2.06-2.16 (2H, q), 2.59 (6H, s), 3.77
(1H, t), 4.02 (2H, t), 6.99 (1H, s), 7.08-7.33 (13H, m), 7.38 (1H,
m).
EXAMPLE 131
[0978] Synthesis of
4-(2,4-dimethylphenyl)-2,6-dimethyl-5-(piperazine-1-ca-
rbonyl)nicotinic acid (3,3-diphenylpropyl) ester:
[0979] 1) Synthesis of
4-[2-acetyl-3-(2,4-dimethylphenyl)-2-propenoyl]-1-p-
iperazinecarboxylic acid t-butyl ester:
[0980] 506 mg (2.71 mmol) of 1-(t-butoxycarbonyl) piperazine, 273
mg (3.23 mmol) of diketene and 0.562 ml (4.07 mmol) of
triethylamine were heated and stirred in 10 ml of toluene at
80.degree. C. for 2 hours. After adding saturated aqueous sodium
hydrogencarbonate solution, the reaction mixture was extracted with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. 364 mg (2.71
mmol) of 2,4-dimethylbenzaldehyde was dissolved in 20 ml of
2-propanol. 16.3 mg (0.271 mmol) of piperidine and 22.3 mg (0.271
mmol) of acetic acid were added and stirred at room temperature for
2 days. After the solvent was evaporated under reduced pressure,
ethyl acetate was added. The obtained substance was washed with 1 N
hydrochloric acid and saturated aqueous sodium hydrogencarbonate
solution. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by the silica gel chromatography (hexane/ethyl
acetate=10/1) to obtain the title compound.
[0981] Yield: 648 mg (2.40 mmol) (89%)
[0982] MS (ESI, m/z) 387 (M+H).sup.+
[0983] .sup.1H-NMR (CDCl3): 1.42 (9H, s), 2.32 (3H, s), 2.36 (3H,
s), 2.43 (3H, s), 2.52-2.65 (1H, m), 2.95-3.33 (4H, m), 3.42-3.78
(3H, m), 6.98 (1H, d), 7.04 (1H, s), 7.40 (1H, d) 7.78 (1H, s).
[0984] 2) Synthesis of
4-[4-(2,4-dimethylphenyl)-5-(3,3-diphenylpropoxycar-
bonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl]
piperazine-1-carboxylic acid-t-butyl ester:
[0985] 648 mg (1.67 mmol) of
4-[2-acetyl-3-(2,4-dimethylphenyl)-2-propenoy-
l]-1-piperazinecarboxylic acid t-butyl ester and 493 mg (1.67 mmol)
of 3-aminocrotonate (3,3-diphenylpropyl) ester were heated and
stirred in 5 ml of 2-propanol at 80.degree. C. for two nights.
After evaporating 2-propanol under reduced pressure, the residue
was purified by the silica gel chromatography (hexane/ethyl
acetate=5/1 to 1/9) to obtain the title compound.
[0986] Yield: 274 mg (0.413 mmol) (25%)
[0987] MS (ESI, m/z) 664 (M+H).sup.+ 662 (M-H).sup.-
[0988] .sup.1H-NMR (CDCl3): 1.42 (9H, s), 1.69 (3H, s), 2.06-2.19
(2H, m), 2.23 (3H, s), 2.28 (3H, s), 2.35 (3H, s), 2.65-2.98 (4H,
m), 3.10-3.21 (1H, m), 3.62 (2H, br t), 3.73-3.89 (2H, m) 5.13 (1H,
br s), 6.83 (1H, s), 6.89-6.97 (2H, m), 7.08-7.27 (10H, m).
[0989] 3) Synthesis of
4-(2,4-dimethylphenyl)-2,6-dimethyl-5-(piperazine-1- -carbonyl)
nicotinic acid (3,3-diphenylpropyl) ester:
[0990] 274 mg (0.413 mmol) of
4-[4-(2,4-dimethylphenyl)-5-(3,3-diphenylpro-
poxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl]
piperazine-1-carboxylic acid-t-butyl ester was dissolved in 10 ml
of dichloromethane. 5 ml of trifluoroacetate was added and stirred
at room temperature for 2 hours. After concentration under reduced
pressure, saturated aqueous sodium hydrogencarbonate solution was
added and the reaction mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (dichloromethane/methanol=100/1 to
10/1) to obtain the title compound.
[0991] Yield: 160 mg (0.285 mmol) (69%)
[0992] MS (ESI, m/z) 562 (M+H).sup.+
[0993] .sup.1H-NMR (CDCl3): 1.85-1.97 (2H, m), 2.13-2.19 (6H, m),
2.52-2.58 (7H, m), 2.68-2.78 (2H, m), 3.01-3.27 (3H, m), 3.55-4.02
(5H, m), 6.81-6.96 (2H, m) 7.06-7.28 (11H, m).
EXAMPLE 132
[0994] Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(morpholine-4-carbon-
yl)nicotinic acid (3,3-diphenylpropyl) ester:
[0995] 50.0 mg (0.100 mmol) of
4-(3-chlorophenyl)-2,6-dimethylpyridine-3,5- -dicarboxylic acid
mono (3,3-diphenylpropyl) ester and 5 ml of thionyl chloride were
stirred in DMF at room temperature for 1 hour. After concentration
under reduced pressure, the residue was dissolved in 3 ml of
dichloromethane. 1 ml of morpholine was added and stirred at room
temperature for 6 hours. After concentration under reduced
pressure, ethyl acetate was added and the residue was washed with
water. The organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by the basic silica gel chromatography (hexane/ethyl
acetate=20/1 to 1/4) to obtain the title compound.
[0996] Yield: 43.9 mg (0.0771 mmol) (77%)
[0997] MS (ESI, m/z) 569 (M+H).sup.+
[0998] .sup.1H-NMR (CDCl3): 1.92-2.08 (2H, m), 2.56 (3H, s), 2.59
(3H, s), 2.77-2.98 (2H, m), 3.02-3.10 (1H, m), 3.18-3.25 (1H, m),
3.38-3.46 (1H, m), 3.49-3.54 (1H, m), 3.57-3.74 (3H, m), 3.85-4.04
(2H, m), 7.06-7.12 (4H, m), 7.14-7.20 (3H, m), 7.24-7.29 (7H,
m).
EXAMPLE 133
[0999] Synthesis of
4-(3-chlorophenyl)-6-methyl-5-(methylpiperazine-1-carb-
onyl)-2-[[2-(pyridine-3-yl) ethoxy] methyl] nicotinic acid
(3,3-diphenylpropyl) ester:
[1000] 114 mg (0.590 mmol) of WSC hydrochloride and 0.066 ml (0.590
mmol) of N-methylpiperazine were added to 307 mg (0.490 mmol) of
4-(3-chlorophenyl)-2-methyl-6-[2-(3-pyridine) ethoxy]
methyl-1,4-dihydropyridine-3,5-dicarboxylic acid
5-(3,3-diphenylpropyl) ester in 10 ml of dichloromethane in the ice
bath and stirred at room temperature overnight. 10 ml of
trifluoroacetate was added and the reaction mixture was stirred at
room temperature overnight. After concentration under reduced
pressure, 1 N aqueous sodium hydroxide solution was added to basify
and the reaction mixture was extracted with ethyl acetate. The
organic layer was dried over anhydrous sodium sulfate and then
concentrated under reduced pressure. The residue was purified by
the basic silica gel chromatography (hexane/ethyl acetate=1/9 to
0/100) to obtain the title compound.
[1001] Yield: 206 mg (0.340 mmol) (66%)
[1002] MS (ESI, m/z) 703 (M++H).sup.+
[1003] .sup.1H-NMR (CDCl3): 1.58-2.06 (4H, m), 2.17 (3H, s),
2.10-2.38 (2H, m), 2.56 (3H, s), 2.73 (2H, t), 2.82-3.14 (2H, m),
3.42-3.64 (2H, m), 3.60 (2H, t), 3.71 (1H, t), 3.76-4.03 (2H, m),
4.60 (1H, d), 4.87 (1H, d), 7.05-7.29 (15H, m), 7.40-7.46 (1H, m),
8.37-8.42 (2H, m).
EXAMPLE 134
[1004] Synthesis of
4-(3,5-dichlorophenyl)-N-(3,3-diphenylpropyl)-2,6-dime-
thyl-5-(1-piperazinylcarbonyl) nicotinamide:
[1005] 1) Synthesis of
4-[5-(2-cyanoethoxycarbonyl)-4-(3,5-dichlorophenyl)-
-2,6-dimethyl-1,4-dihydropyridine-3-carbonyl]
piperazine-1-carboxylic acid-t-butyl ester:
[1006] 1.66 g (3.88 mmol) of
4-[2-acetyl-3-(3,5-dichlorophenyl)-2-propenoy- l]
piperazine-1-carboxylic acid t-butyl ester and 598 mg (3.88 mmol)
of 3-aminocrotonate 2-cyanoethyl ester were stirred in 30 ml of
2-propanol at 80.degree. C. overnight and then stirred at
120.degree. C. for 2 hours. After concentration under reduced
pressure, ethyl acetate was added and the residue was washed with
saturated aqueous sodium chloride solution. The organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by the silica gel
chromatography (dichloromethane/methanol=100/1 to 30/1) to obtain
the title compound.
[1007] Yield: 1.31 g (2.32 mmol) (60%)
[1008] MS (ESI, m/z) 561 (M-H).sup.-
[1009] .sup.1H-NMR (CDCl3): 1.44 (9H, s), 1.78 (3H, s), 2.40 (3H,
s), 2.50 (2H, br t), 2.75-3.82 (6H, m), 4.08-4.15 (4H, m), 4.86
(1H, br s), 5.41 (1H, br s), 7.10 (2H, d), 7.20 (1H, t).
[1010] 2) Synthesis of
4-[5-carboxy-4-(3,5-dichlorophenyl)-2,6-dimethyl-1,-
4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic acid t-butyl
ester:
[1011] The title compound was was obtained by using 1.31 g (2.32
mmol) of
4-[5-cyanoethoxycarbonyl)-4-(3,5-dichlorophenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3-carbonyl] piperazine-1-carboxylic acid-t-butyl ester and
4.64 ml (4.64 mmol) of 1 N aqueous sodium hydroxide solution, in
the same manner as that of Example 123 2).
[1012] Yield: 1.10 g (2.16 mmol) (93%)
[1013] MS (ESI, m/z) 508 (M-H).sup.-
[1014] .sup.1H-NMR (DMSO-d6): 1.36 (9H, s), 1.68 (3H, s), 2.25 (3H,
s), 2.99-3.56 (8H, m), 4.78 (1H, s), 7.16 (2H, d), 7.27-7.28 (1H,
m), 7.64 (1H, br s).
[1015] 3) Synthesis of
4-[4-(3,5-dichlorophenyl)-2,6-dimethyl-5-(3,3-diphe-
nylpropylcarbamoyl) pyridine-3-carbonyl] piperazine-1-carboxylic
acid t-butyl ester:
[1016] 300 mg (0.588 mmol) of
4-[5-carboxy-4-(3,5-dichlorophenyl)-2,6-dime-
thyl-1,4-dihydropyridine-3-carbonyl] piperazine-1-carboxylic acid
t-butyl ester, 0.12 ml (0.882 mmol) of 3,3-diphenylpropylamine and
248 mg (1.29 mmol) of WSC hydrochloride were stirred in 15 ml of
dichloromethane and 1 ml of DMF at room temperature overnight.
After dichloromethane was evaporated under reduced pressure, ethyl
acetate was added. After being washed with saturated aqueous sodium
hydrogencarbonate solution and 1 N hydrochloric acid, the organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was dissolved in 8
ml of acetone. 811 mg (1.48 mmol) of diammonium cerium nitrate (IV)
suspended in 8 ml of water was dropped and stirred at room
temperature for 1 hour. After acetone was evaporated under reduced
pressure, ethyl acetate was added. After being washed with water,
the organic layer was dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by the silica gel chromatography (dichloromethane/methanol=100/1 to
80/1) to obtain the title compound.
[1017] Yield: 369 mg (0.526 mmol) (90%)
[1018] MS (ESI, m/z) 699 (M-H).sup.-
[1019] .sup.1H-NMR (CDCl3): 1.42 (9H, s), 1.82-1.96 (2H, m), 2.51
(3H, s), 2.57 (3H, s), 2.66-3.01 (5H, m), 3.20-3.54 (6H, m), 5.35
(1H, br t), 7.08-7.11 (4H, m), 7.15-7.30 (7H, m), 7.36 (2H, br
s).
[1020] 4) Synthesis of
4-(3,5-dichlorophenyl)-N-(3,3-diphenylpropyl)-2,6-d-
imethyl-5-(1-piperazinylcarbonyl) nicotinamide:
[1021] The title compound was obtained by using 362 mg (0.516 mmol)
of
4-[4-(3,5-dichlorophenyl)-2,6-dimethyl-5-(3,3-diphenylpropylcarbamoyl)
pyridine-3-carbonyl] piperazine-1-carboxylic acid t-butyl ester and
5 ml of trifluoroacetate, in the same manner as that of Example 124
3).
[1022] Yield: 244 mg (0.406 mmol) (79%)
[1023] MS (ESI, m/z) 601 (M+H).sup.+
[1024] .sup.1H-NMR (CDCl3): 1.65-1.97 (2H, m), 2.14-2.21 (1H, m),
2.42-2.64 (9H, m), 2.75-2.93 (3H, m), 2.95-3.04 (1H, m), 3.31-3.42
(1H, m), 3.48-3.54 (3H, m), 3.89 (1H, br t), 7.08-7.11 (4H, m),
7.14-7.20 (3H, m), 7.24-7.30 (4H, m), 7.33-7.39 (2H, br s).
EXAMPLE 135
[1025] Synthesis of
4-(2,4-dimethylphenyl)-2,6-dimethyl-5-(4-methylpiperaz-
ine-1-carbonyl)nicotinic acid (3,3-diphenylpropyl) ester:
[1026] 169 mg (0.301 mmol) of
4-(2,4-dimethylphenyl)-2,6-dimethyl-5-(piper-
azine-1-carbonyl)nicotinic acid (3,3-diphenylpropyl) ester was
dissolved in 10 ml of DMF. 62.4 mg (01.301 mmol) of potassium
carbonate was added and stirred for 30 minutes. 51.3 mg (0.361
mmol) of methyl iodide was added under cooling with ice and stirred
at the same temperature for 1 hour. The reaction mixture was
further stirred for 10 minutes after adding water. After
evaporating DMF under reduced pressure, the reaction mixture was
diluted with ethyl acetate and washed with saturated aqueous sodium
chloride solution. The organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by the silica gel chromatography
(dichloromethane/methanol=50/1 to 10/1) to obtain the title
compound.
[1027] Yield: 9.50 mg (0.0165 mmol) (5.5%)
[1028] MS (ESI, m/z) 433 (M+H).sup.+
[1029] .sup.1 H-NMR (CDCl3): 1.86-1.99 (2H, m), 2.15-2.24 (12H, m),
2.53-2.59 (6H, m), 3.03-3.22 (3H, m), 3.66-4.02 (5H, m), 6.80-6.98
(2H, m), 7.03-7.28 (11H, m).
EXAMPLE 136
[1030] Synthesis of
4-(2,5-dimethylphenyl)-2,6-dimethyl-5-(piperazine-1-ca-
rbonyl)nicotinic acid (3,3-diphenylpropyl) ester:
[1031] The title compound was obtained by using 826 mg (2.14 mmol)
of
4-[2-acetyl-3-(2,5-dimethylphenyl)-2-propenoyl]-1-piperazinecarboxylic
acid t-butyl ester and 632 mg (2.14 mmol) of 3-aminocrotonate
(3,3-diphenylpropyl) ester, in the same manner as that of Example
131.
[1032] Yield: 329 mg (0.586 mmol) (27%) (2 steps)
[1033] MS (ESI, m/z) 562 (M+H).sup.+
[1034] .sup.1H-NMR (CDCl3): 1.78-1.94 (2H, m), 2.12 (3H, s), 2.19
(3H, s), 2.57-2.71 (8H, m), 2.97-3.13 (2H, m), 3.29-3.49 (2H, m),
3.58-3.73 (2H, m), 3.76-3.97 (3H, m), 6.68 (1H, s), 7.03-7.29 (13H,
m).
EXAMPLE 137
[1035] Synthesis of
4-(4-chlorophenyl)-2,6-dimethyl-5-(piperazine-1-carbon-
yl)nicotinic acid (3,3-diphenylpropyl) ester:
[1036] The title compound was obtained by using 774 mg (1.97 mmol)
of
4-[2-acetyl-3-(4-chlorophenyl)-2-propenoyl]-1-piperazinecarboxylic
acid t-butyl ester and 582 mg (1.97 mmol) of 3-aminocrotonate
(3,3-diphenylpropyl) ester, in the same manner as that of Example
131.
[1037] Yield: 337 mg (0.593 mmol) (30%) (2 steps)
[1038] MS (ESI, m/z) 568 (M+H).sup.+
[1039] .sup.1H-NMR (CDCl3): 1.87-2.08 (3H, m), 2.24-2.32 (1H, m),
2.52 (3H, s), 2.58 (3H, s), 2.76-2.84 (1H, m), 3.00-3.05 (2H, m),
3.22-3.31 (1H, m), 3.62-3.78 (3H, m), 3.85-4.00 (2H, m), 7.05-7.30
(14H, m).
EXAMPLE 138
[1040] Synthesis of
4-(2,5-dimethylphenyl)-2,6-dimethyl-5-(4-methylpiperaz-
ine-1-carbonyl)nicotinic acid (3,3-diphenylpropyl) ester:
[1041] The title compound was obtained by using 236 mg (0.420 mmol)
of
4-(2,5-dimethylphenyl)-2,6-dimethyl-5-(piperazine-1-carbonyl)nicotinic
acid (3,3-diphenylpropyl) ester, 59.6 mg (0.420 mmol) of methyl
iodide and 69.7 mg (0.504 mmol) of potassium carbonate, in the same
manner as that of Example 135.
[1042] Yield: 126 mg (0.219 mmol) (52%)
[1043] MS (ESI, m/z) 576 (M+H).sup.+
[1044] .sup.1H-NMR (CDCl3): 1.81-2.08 (3H, m), 2.12-2.29 (11H, m),
2.52-2.60 (7H, m), 3.04-3.23 (2H, m), 3.30-3.39 (1H, m), 3.52-3.61
(1H, m), 3.73 (1H, t), 3.80-3.94 (2H, m), 6.73 (1H, s), 6.96-7.28
(12H, m).
EXAMPLE 139
[1045] Synthesis of
4-(2-chlorophenyl)-2,6-dimethyl-5-(piperazine-1-carbon-
yl)nicotinic acid (3,3-diphenylpropyl) ester:
[1046] The title compound was obtained by using 731 mg (1.86 mmol)
of
4-[2-acetyl-3-(2-chlorophenyl)-2-propenoyl]-1-piperazinecarboxylic
acid t-butyl ester and 550 mg (1.86 mmol) of 3-aminocrotonate
(3,3-diphenylpropyl) ester, in the same manner as that of Example
131.
[1047] Yield: 35.6 mg (0.0627 mmol) (3.4%) (2 steps)
[1048] MS (ESI, m/z) 568 (M+H).sup.+
[1049] .sup.1H-NMR (CDCl3): 1.67-2.06 (2H, m), 2.28-2.44 (2H, m),
2.53-2.66 (7H, m), 2.71-2.80 (1H, m), 3.09-3.13 (2H, m), 3.34-3.52
(2H, m), 3.76-3.98 (3H, m), 7.09-7.30 (14H, m).
EXAMPLE 140
[1050] Synthesis of
4-(4-chorophenyl)-2,6-dimethyl-5-(4-methylpiperazine-1-
-carbonyl)nicotinic acid (3,3-diphenylpropyl) ester:
[1051] The title compound was obtained by using 131 mg (0.231 mmol)
of
4-(4-chlorophenyl)-2,6-dimethyl-5-(piperazine-1-carbonyl)nicotinic
acid (3,3-diphenylpropyl) ester, 32.7 mg (0.231 mmol) of methyl
iodide and 38.3 mg (0.277 mmol) of potassium carbonate, in the
same, manner as that of Example 135.
[1052] Yield: 81.2 mg (0.139 mmol) (60%)
[1053] MS (ESI, m/z) 582 (M+H).sup.+
[1054] .sup.1H-NMR (CDCl3): 1.70-1.76 (2H, m), 1.85-2.13 (3H, m),
2.15 (3H, s), 2.24-2.31 (1H, m), 2.55 (3H, s), 2.58 (3H, s),
2.71-2.78 (1H, m), 3.00-3.08 (1H, m), 3.31-3.39 (1H, m), 3.05-3.68
(1H, m), 3.74 (1H, t), 3.83-3.99 (2H, m), 7.05-7.12 (4H, m),
7.14-7.20 (2H, m), 7.24-7.29.(8H, m).
EXAMPLE 141
[1055] Synthesis of 4-(3-chlorophenyl)-5-[(3,3-diphenylpropoxy)
carbonyl]-2-methyl-6-[[2-(pyridine-3-yl)ethoxy] methyl] nicotinic
acid:
[1056] 2 ml of acetone was added to 80.0 mg (0.130 mmol) of
4-(3-chlorophenyl)-2-methyl-6-[2-(3-pyridine) ethoxy]
methyl-1,4-dihydropyridine-3,5-dicarboxylic acid
5-(3,3-diphenylpropyl) ester. 170 mg (0.310 mmol) of diammonium
cerium nitrate (IV) suspended in 1 ml of water was added and
stirred at room temperature for 30 minutes. After adding water, the
reaction mixture was extracted with ethyl acetate. The organic
layer was dried over anhydrous sodium sulfate and then concentrated
under reduced pressure to obtain the title compound.
[1057] Yield: 68.0 mg (0.110 mmol) (85%)
[1058] MS (ESI, m/z) 619 (M-H).sup.-
[1059] .sup.1H-NMR (DMSO-d6): 1.94-2.09 (2H, m), 2.54 (3H, s), 2.93
(2H, t), 3.66 (2H, t), 3.71 (1H, t), 3.84 (1H, t), 4.66 (2H, s),
7.13-7.32 (12H, m), 7.40 (1H, t), 7.46-7.50 (1H, m), 7.96 (1H, t),
8.38 (1H, d), 8.70-8.82 (2H, m).
EXAMPLE 142
[1060] Synthesis of
4-(3-fluorophenyl)-2,6-dimethyl-5-piperazine-1-carbony- l)nicotinic
acid (3,3-diphenylpropyl) ester:
[1061] The title compound was obtained by using 471 mg (1.25 mmol)
of
4-[2-acetyl-3-(3-fluorophenyl)-2-propenoyl]-1-piperazinecarboxylic
acid t-butyl ester and 369 mg (1.25 mmol) of 3-aminocrotonate
(3,3-diphenylpropyl) ester, in the same manner as that of Example
131.
[1062] Yield: 45.8 mg (0.0830 mmol) (6.6%) (2 steps)
[1063] MS (ESI, m/z) 552 (M+H).sup.+
[1064] .sup.1H-NMR (CDCl3): 1.88-2.08 (2H, m), 2.13-2.23 (1H, m),
2.43-2.62 (8H, m), 2.74-2.83 (2H, m), 2.99-3.06 (1H, m), 3.37-3.46
(1H, m), 3.51-3.58 (1H, m), 3.72 (1H, t), 3.84-3.98 (2H, m),
6.93-7.00 (1H, m), 7.06-7.29 (13H, m).
EXAMPLE 143
[1065] Synthesis of
4-(3-chlorophenyl)-5-(1,4-diazepan-1-carbonyl)-2,6-dim-
ethylnicotinic acid (3,3-diphenylpropyl) ester:
[1066] 200 mg (0.398 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydrop-
yridine-3,5-dicarboxylic acid mono (3,3-diphenylpropyl) ester, 120
mg (1.20 mmol) of homopiperazine and 230 mg (1.20 mmol) of WSC
hydrochloride were stirred in 6 ml of dichloromethane at room
temperature overnight. 0.8 ml of DMF was added and stirred at
60.degree. C. for 5 hours. After concentration under reduced
pressure, chloroform was added. After being washed with saturated
aqueous sodium hydrogencarbonate solution, the organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The obtained substance was dissolved in 5 ml of
dichloromethane. 2 ml of trifluoroacetate was added and stirred at
room temperature for 30 minutes. After concentration under reduced
pressure, ethyl acetate was added and the reaction mixture was
washed with saturated aqueous sodium hydrogencarbonate solution.
The organic layer was dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by the thin layer silica gel chromatography
(dichloromethane/methanol=9/1) to obtain the title compound.
[1067] Yield: 36.8 mg (0.0632 mmol) (16%)
[1068] MS (ESI, m/z) 582 (M+H).sup.+
[1069] .sup.1H-NMR (CDCl3): 1.60-1.72 (1H, m), 1.78-2.09 (4H, m),
2.54-2.62 (7H, m), 2.82-2.97 (2H, m), 3.05-3.20 (2H, m), 3.42-3.55
(2H, m), 3.70 (1H, t), 3.88 (2H, dt), 3.93-4.03 (1H, m), 7.05-7.12
(4H, m), 7.14-7.29 (10H, m).
EXAMPLE 144
[1070] Synthesis of
4-(3-chlorophenyl)-5-(4-hydroxypiperidine-1-carbonyl)--
2,6-dimethylnicotinic acid (3,3-diphenylpropyl) ester:
[1071] The title compound was obtained by using 200 mg (0.398 mmol)
of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic
acid mono (3,3-diphenylpropyl) ester, 80.9 mg (0.797 mmol) of
4-hydroxypiperazine and 2.0 ml of trifluoroacetate, in the same
manner as that of Example 143.
[1072] Yield: 135 mg (0.232 mmol) (58%)
[1073] MS (ESI, m/z) 583 (M+H).sup.+
[1074] .sup.1H-NMR (CDCl3): 1.28-1.43 (1H, m), 1.46-1.70 (3H, m),
1.72-1.84 (1H, m), 1.90-2.06 (2H, m), 2.54 (3H, d), 2.58 (3H, s),
2.63-2.96 (1H, m), 3.08-3.3o (2H, m), 3.71 (1H, t), 3.75-3.81 (1H,
m), 3.84-4.02 (3H, m), 7.06-7.29 (14H, m).
EXAMPLE 145
[1075] Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-pyrimidine--
5-carboxylic acid 3-phenylpropyl ester:
[1076] 1) Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-1,4-dihy-
dropyridine-5-carboxylic acid 3-phenylpropyl ester:
[1077] 200 mg (0.583 mmol) of 2-acetyl-3-(3-chlorophenyl) acrylic
acid 3-phenylpropyl ester was dissolved in 10 ml of DMF. 130 mg
(0.467 mmol) of methylisothiourea-sulfate and 95.6 mg (1.17 mmol)
of sodium acetate was added at room temperature and stirred at
60.degree. C. for 2 days. After DMF was evaporated under reduced
pressure, the reaction mixture was diluted -with ethyl acetate and
washed with saturated aqueous sodium chloride solution. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=10/1 to 2/1) to
obtain the title compound.
[1078] Yield: 193 mg (0.465 mmol) (80%)
[1079] MS (ESI, m/z) 415 (M+H).sup.+ 413 (M-H).sup.-
[1080] .sup.1H-NMR (CDCl3): 1.84-1.93 (2H, m), 2.36 (3H, s), 2.42
(3H, s), 2.56 (2H, t), 4.02-4.11 (2H, m), 5.72 and 6.26 (total 1H,
ratio 1:1, br s, br s, respectively), 7.07-7.10 (2H, m), 7.17-7.31
(7H, m).
[1081] 2) Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-pyrimidi-
ne-5-carboxylic acid 3-phenylpropyl ester:
[1082] 88.5 mg (0.213 mmol) of
4-(3-dichlorophenyl)-2-(methylthio)-1,4-dih-
ydropyrimidine-5-carboxylic acid 3-phenylpropyl ester was dissolved
in 5 ml of toluene. 96.8 mg (0.427 mmol) of
2,3-dichloro-5,6-dicyano-1,4-benzo- chinon (hereinafter abbreviated
as DDQ) was added and stirred at 50.degree. C. for 1 hour. After
filtration of insoluble matters, the filtrate was diluted with
ethyl acetate. The organic layer was washed with saturated aqueous
sodium chloride solution and dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by the silica gel chromatography (hexane/ethyl
acetate=10/1 to 3/1) to obtain the title compound. Yield: 46.0 mg
(0.111 mmol) (52%)
[1083] MS (ESI, m/z) 413 (M+H).sup.+
[1084] .sup.1H-NMR (CDCl3): 1.75 (2H, quint), 2.38 (2H, t), 2.58
(3H, s), 2.62 (3H, s), 4.13 (2H, t), 7.04 (2H, d), 7.15-7.28 (3H,
m), 7.32-7.43 (2H, m), 7.50 (1H, d), 7.66 (1H, s).
EXAMPLE 146
[1085] Synthesis of
4-(3-chlorophenyl)-6-(methoxymethyl)-2-(methylthio)-py-
rimidine-5-carboxylic acid 3-phenylpropyl ester:
[1086] The title compound was obtained by using 170 mg (0.456 mmol)
of 3-(3-chlorophenyl)-2-(methoxyacetyl)-2-acrylic acid
3-phenylpropyl ester, 96.0 mg (0.345 mmol) of
methylisothiourea-sulfate and 75.5 mg (0.920 mmol) of sodium
acetate, in the same manner as that of Example 145.
[1087] Yield: 39.6 mg (0.0894 mmol) (20%) (2 steps)
[1088] MS (ESI, m/z) 443 (M+H).sup.+
[1089] .sup.1H-NMR (CDCl3): 1.81 (2H, m), 2.43 (2H, t), 2.63 (3H,
s), 3.37 (3H, s), 4.14 (2H, t), 4.65 (2H, s), 7.07 (2H, d),
7.18-7.45 (5H, m), 7.51-7.54 (1H, m), 7.67-7.69 (1H, m).
EXAMPLE 147
[1090] Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-pyrimidine--
5-carboxylic acid (3,3-diphenylpropyl) ester:
[1091] The title compound was obtained by using 500 mg (1.19 mmol)
of 2-acetyl-3-(3-chlorophenyl)-2-acrylic acid (3,3-diphenylpropyl)
ester, 169 mg (1.79 mmol) of acetamidine hydrochloride and 195 mg
(2.38 mmol) of sodium acetate, in the same manner as that of
Example 145.
[1092] Yield: 253 mg (0.517 mmol) (44%) (2 steps)
[1093] MS (ESI, m/z) 489 (M+H).sup.+
[1094] .sup.1H-NMR (CDCl3): 2.16 (2H, q), 2.55 (3H, s), 2.62 (3H,
s), 3.78 (1H, t), 4.08 (2H, t), 7.10-7.21 (6H, m), 7.24-7.29 (5H,
m), 7.36 (1H, dt), 7.46 (1H, dt), 7.67 (1H, t).
EXAMPLE 148
[1095] Synthesis of
N-[4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimi-
dinyl]-3-phenylpropanamide:
[1096] 1) Synthesis of 2-acetyl-3-(3-chlorophenyl) acrylic acid
ethylester:
[1097] 5.00 g (38.4 mmol) of acetoacetic acid and 5.40 g (38.4
mmol) of 3-chlorobenzaldehyde were dissolved in 50 ml of
2-propanol. 327 mg (3.84 mmol) of piperidine and 231 mg (3.84 mmol)
of acetic acid were added and stirred at room temperature for one
day. After the solvent was evaporated, ethyl acetate was added and
the reaction mixture was washed with 1 N hydrochloric acid and
saturated aqueous sodium hydrogencarbonate solution. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=5/1) to obtain
the title compound.
[1098] Yield: 9.45 g (37.4 mmol) (97%)
[1099] MS (ESI, m/z) 253 (M+H).sup.+
[1100] .sup.1H-NMR (CDCl3): 1.29 (3H, t), 2.42 (3H, s), 4.34 (2H,
q), 7.32-7.40 (3H, m), 7.44 (1H, br), 7.50 (1H, s).
[1101] 2) Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-1,4-dihy-
dropyrimidine-5-carboxylic acid ethylester:
[1102] 3.33 g (13.2 mmol) of 2-acetyl-3-(3-chlorophenyl) acrylic
acid ethylester was dissolved in 30 ml of n-butanol. 2.93 g (10.5
mmol) of methylisothiourea-sulfate and 2.00 g (19.8 mmol) of
triethylamine were added at room temperature and stirred at
100.degree. C. for one day. After n-butanol was evaporated under
reduced pressure, the reaction mixture was diluted with ethyl
acetate and washed with saturated aqueous sodium chloride solution.
The organic layer was dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by the silica gel chromatography (hexane/ethyl acetate=10/1) to
obtain the title compound.
[1103] Yield: 2.09 g (6.42 mmol) (49%)
[1104] MS (ESI, m/z) 325 (M+H).sup.+ 323 (M-H).sup.-
[1105] .sup.1H-NMR (CDCl3): 1.21 (3H, t), 2.32 (3H, s), 2.41 (3H,
s), 4.11 (2H, q), 5.70 (1H, s), 6.28 (1H, br s), 7.19-7.28 (4H,
m).
[1106] 3) Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimi- dinecarboxylic
acid ethylester:
[1107] 2.09 g (6.43 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-1,-
4-dihydropyrimidine-5-carboxylic acid ethylester was dissolved in
30 ml of chloroform. 8.39 g (96.5 mmol) of manganese dioxide was
added at room temperature and stirred at 80.degree. C. for 2 hours.
After filtration of insoluble matters, the obtained filtrate was
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain
the title compound.
[1108] Yield: 1.44 g (4.47 mmol) (70%)
[1109] MS (ESI, m/z) 323 (M+H).sup.+
[1110] .sup.1H-NMR (CDCl3): 1.10 (3H, t), 2.57 (3H, s), 2.61 (3H,
s), 4.19 (2H, q), 7.34-7.52 (3H, m), 7.64-6.65 (1H, m).
[1111] 4) Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimi- dinecarboxylic
acid:
[1112] 1.44 g (4.47 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-- pyrimidinecarboxylic
acid ethylester was dissolved in 10 ml of THF and 5 ml of water.
225 mg (5.36 mmol) of lithium hydroxide monohydrate was added and
stirred at 50.degree. C. for 12 hours. 10 ml of water was added
thereto and the organic layer was batched off. The obtained aqueous
layer was diluted with ethyl acetate and washed with 5 ml of 3 N
hydrochloric acid and then with 5 ml of saturated aqueous sodium
chloride solution. The organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure to
obtain the title compound.
[1113] Yield: 1.21 g (4.11 mmol) (92%)
[1114] MS (ESI, m/z) 293 (M-H).sup.-
[1115] .sup.1H-NMR (CDCl3): 2.56 (3H, s), 2.62 (3H, s), 7.38-7.49
(2H, m), 7.54-7.68 (1H, m), 7.70-7.72 (1H, m).
[1116] 5) Synthesis of t-butyl
4-methyl-6-(methylphenyl)-2-(methylthio)-5-- pyrimidinyl
carbamate:
[1117] 871 mg (2.95 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-- pyrimidinecarboxylic
acid was dissolved in 20 ml of t-butanol. 448 mg (4.43 mmol) of
triethylamine and 1.22 g (4.43 mmol) of diphenylphosphorylazide
were added at room temperature and stirred at 100.degree. C. for 3
hours. After t-butanol was evaporated under reduced pressure, the
reaction mixture was diluted with ethyl acetate and washed with
saturated aqueous sodium chloride solution. The organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by the silica gel
chromatography (hexane/ethyl acetate=10/1) to obtain the title
compound.
[1118] Yield: 140 mg (0.383 mmol) (13%)
[1119] MS (ESI, m/z) 366 (M+H).sup.+ 364 (M-H).sup.-
[1120] .sup.1H-NMR (CDCl3): 1.45 (9H, s), 2.51 (3H, s), 2.58 (3H,
s), 5.75 (2H, br), 7.32-7.43 (2H, m), 7.55-7.58 (1H, m), 7.65 (1H,
br s).
[1121] 6) Synthesis of
4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimi- dinamine:
[1122] 10 ml of 4 N hydrochloric acid-ethyl acetate solution was
added to 125 mg (0.342 mmol) of t-butyl
4-methyl-6-(methylphenyl)-2-(methylthio)-5- -pyrimidinyl carbamate
under cooling with ice and stirred at room temperature for one day.
1 ml of trifluoroacetate was added thereto and stirred at
50.degree. C. for 12 hours. After the solvent was evaporated under
reduced pressure, the reaction mixture was diluted with ethyl
acetate and washed with saturated aqueous sodium hydrogencarbonate
solution and saturated aqueous sodium chloride solution. The
organic layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to obtain the title
compound.
[1123] Yield: 91.0 mg (0.342 mmol) (quantitative yield)
[1124] MS (ESI, m/z) 266 (M+H).sup.+
[1125] .sup.1H-NMR (CDCl3): 2.44 (3H, s), 2.56 (3H, s), 7.42-7.43
(2H, m), 7.61-7.63 (1H, m), 7.73-7.74 (1H, m).
[1126] 7) Synthesis of
N-[4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyr-
imidinyl]-3-phenylpropanamide:
[1127] 51.4 mg (0.342 mmol) of 3-phenylpropionic acid was dissolved
in 1 ml of thionyl chloride. A catalytic amount of DMF was added
and stirred at room temperature for 3 hours. After the solvent was
evaporated under reduced pressure, 45.4 mg (0.171 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(- methylthio)-5-pyrimidinamine and 1
ml of pyridine were added and stirred at 50.degree. C. overnight.
After the solvent was evaporated under reduced pressure, the
reaction mixture was diluted with ethyl acetate and washed with
saturated aqueous sodium chloride solution. The organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by the silica gel
chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the
title compound.
[1128] Yield: 10.6 mg (0.0266 mmol) (16%)
[1129] MS (ESI, m/z) 398 (M+H).sup.+ 396 (M-H).sup.-
[1130] .sup.1H-NMR (CDCl3): 2.31 (3H, s), 2.38 (2H, t), 2.57 (3H,
s), 2.62 (2H, t), 6.58 (1H, br), 7.17-7.49 (8H, m), 7.56-7.57 (1H,
m).
EXAMPLE 149
[1131] Synthesis of
N-[4-(3-chlorophenyl)-6-methyl-2-(methylthio)-5-pyrimi-
dinyl]-4-phenylbutanamide:
[1132] 56.2 mg (0.342 mmol) of 4-phenylbutyric acid was dissolved
in 1 ml of thionyl chloride. A catalytic amount of DMF was added
and stirred at room temperature for 3 hours. After the solvent was
evaporated under reduced pressure, 45.4 mg (0.171 mmol) of
4-(3-chlorophenyl)-6-methyl-2-(- methylthio)-5-pyrimidinamine and 1
ml of pyridine were added and stirred at 50.degree. C. overnight.
After the solvent was evaporated under reduced pressure, the
reaction mixture was diluted with ethyl acetate and washed with
saturated aqueous sodium chloride solution. The organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by the silica gel
chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the
title compound.
[1133] Yield: 12.3 mg (0.0299 mmol) (18%)
[1134] MS (ESI, m/z) 412 (M+H).sup.+ 410 (M-H).sup.-
[1135] .sup.1H-NMR (CDCl3): 2.00 (3H, quint), 2.29 (2H, t), 2.44
(3H, s), 2.58 (3H, s), 2.65 (2H, t), 7.14-7.47 (8H, m), 7.56-7.57
(1H, m).
EXAMPLE 150
[1136] Synthesis of 4-(3-chlorophenyl)-6-[(2-hexylethoxy)
methyl]-2-phenylpyrimidine-5-carboxylic acid 3,3-diphenylpropyl
ester:
[1137] 1) Synthesis of 3-(3-chlorophenyl)-2-[(2-cyclohexylethoxy)
acetyl]-2-propenoic acid 3,3-diphenylpropyl ester:
[1138] 1.23 g (2.90 mmol) of 4-(2-cyclohexylethoxy)-3-oxobutanoic
acid 3,3-diphenylpropyl ester, 0.33 ml (2.91 mmol) of
3-chlorobenzaldehyde, 0.05 ml (0.51 mmol) of piperidine and
catalytic amount of p-toluenesulfonic acid were refluxed in 20 ml
of benzene removing water for 1.5 hours. After adding ethyl
acetate, the organic layer was washed with 1 N hydrochloric acid
and saturated aqueous sodium hydrogencarbonate solution, and dried
over anhydrous sodium sulfate and then concentrated under reduced
pressure to obtain the title compound.
[1139] Yield: 1.59 g (2.91 mmol) (quantitative yield)
[1140] 2) Synthesis of 4-(3-chlorophenyl)-6-[(2-cyclohexylethoxy)
acetyl]-2-phenyl-1,4-dihydropyrimidine-5-carboxylic acid
3,3-diphenylpropyl ester:
[1141] 194 mg (1.24 mmol) of benzamidine hydrochloride and 179 mg
(1.30 mmol) of potassium carbonate were heated and stirred in 5 ml
of DMF at 60.degree. C. for 1 hour. 670 mg (1.23 mmol) of
3-(3-chlorophenyl)-2-[(2-- cyclohexylethoxy) acetyl]-2-propenoic
acid 3,3-diphenylpropyl ester dissolved in 5 ml of DMF was added
thereto, heated and stirred at 60.degree. C. overnight. After DMF
was evaporated under reduced pressure, 1 N hydrochloric acid was
added and the reaction mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous sodium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (hexane/ethyl acetate=4/1) to obtain
the title compound.
[1142] Yield: 245 mg (0.38 mmol) (31%)
[1143] MS (ESI, m/z) 645 (M-H).sup.-
[1144] 1H-NMR (CDCl3): 0.86-1.79 (13H, m), 2.31 (2H, qua), 3.64
(2H, t), 3.88 (1H, t), 3.99 (2H, t), 4.79 (2H, qua), 5.85 (1H, s),
7.04-7.10 (2H, m), 7.12-7.37 (11H, m), 7.40-7.52 (4H, m), 7.70-7.87
(2H, m), 8.21 (1H, s).
[1145] 3) Synthesis of 4-(3-chlorophenyl)-6-[(2-cyclohexylethoxy)
methyl]-2-phenylpyrimidine-5-carboxylic acid 3,3-diphenylpropyl
ester:
[1146] 89.8 mg (0.14 mmol) of
4-(3-chlorophenyl)-6-[(2-cyclohexylethoxy)
methyl]-2-phenyl-1,4-dihydropyrimidine-5-carboxylic acid
3,3-diphenylpropyl ester and 94.3 mg (0.42 mmol) of
2,3-dichloro-5,6-dicyano-1,4-benzochinon (DDQ) were refluxed in 20
ml of benzene for 3 hours. After adding water, the reaction mixture
was extracted with ethyl acetate. The organic layer was dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure. The residue was purified by the silica gel chromatography
(hexane/ethyl acetate=9/1) to obtain the title compound.
[1147] Yield: 68 mg (0.105 mmol) (76%)
[1148] MS (ESI, m/z) 645 (M+H).sup.+
[1149] 1H-NMR (CDCl3): 0.74-1.68 (13H, m), 2.24 (2H, qua), 3.48
(2H, t), 3.82 (1H, t), 4.09-4.16 (2H, m), 4.80 (2H, s), 7.11-7.42
(12H, m), 7.47-7.59 (4H, m), 7.79 (1H, t), 8.53-8.58 (2H, m).
EXAMPLE 151
[1150] Synthesis of 4-(3-chlorophenyl)-5-(3-(4-(5H-dibenzo[a,d]
cyclohepten-5-ylidene) piperidine-1-yl) propoxy)
carbonyl-2,6-dimethylnic- otinic acid:
[1151] 1) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid 3-(2-cyanoethyl) ester
5-(3-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene) piperidine-1-yl)
propan-1-yl) ester:
[1152] 366 mg (0.88 mmol) of acetoacetic acid 3-(4-(5H-dibenzo[a,d]
cyclohepten-5-ylidene) piperidine-1-yl) propyl ester and 136 mg
(1.76 mmol) of ammonium acetate were heated and stirred in 10 ml of
2-propanol at 60.degree. C. for 2 days. After 2-propanol was
evaporated, ethyl acetate was added and the reaction mixture was
washed with saturated aqueous sodium hydrogencarbonate solution.
The organic layer was dried over anhydrous sodium sulfate and then
concentrated under reduced pressure. 10 ml of 2-propanol and 245 mg
(0.88 mmol) of 2-(3-chlorobenzylidene) acetoacetic acid
2-cyanoethyl were added to the residue and the residue was
heat-refluxed for 4 hours. After evaporating 2-propanl, the residue
was purified by the basic silica gel chromatography (hexane/ethyl
acetate=9/1 to 1/9) to obtain the title compound.
[1153] Yield: 339 mg (0.503 mmol) (57%)
[1154] MS (ESI, m/z) 674 (M+H).sup.+
[1155] 1H-NMR (CDCl3): 1.67-2.39 (10H, m), 2.34 (6H, s), 2.44-2.57
(2H, m), 2.61 (2H, t), 3.98-4.16 (2H, m), 4.17-4.32 (2H, m), 4.93
(1H, s), 5.72 (1H, s), 6.92 (2H, s), 7.06-7.38 (12H, m).
[1156] 2) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid mono (3-(4-(5H-dibenzo[a,d]
cyclohepten-5-ylidene) piperidine-1-yl) propan-1-yl) ester:
[1157] 5 ml of methanol and 0.434 ml of 1 N aqueous sodium
hydroxide solution were added to 244 mg (0.36 mmol) of
4-(3-chlorophenyl)-2,6-dimet-
hyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl)
ester 5-(3-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)
piperidine-1-yl) propan-1-yl) ester and stirred at room temperature
for 5 hours. After adding 1 N hydrochloric acid, precipitates were
taken by the filtration and dried under reduced pressure to obtain
the title compound.
[1158] Yield: 202 mg (0.325 mmol) (90%)
[1159] MS (ESI, m/z) 621 (M+H).sup.+
[1160] 1H-NMR (DMSO): 1.55-1.72 (2H, m), 1.88-2.08 (4H, m),
2.10-2.29 (4H, m), 2.21 (3H, s), 2.25 (3H,s), 2.33-2.46 (2H, m),
3.84-4.05 (2H, m), 4.83 (1H, s), 6.95 (2H, s), 7.05-7.38 (12H, m),
8.79 (1H, s).
[1161] 3) Synthesis of 4-(3-chlorophenyl)-5-(3-(4-(5H-dibenzo[a,d]
cyclohepten-5-ylidene) piperidine-1-yl) propoxy)
carbonyl-2,6-dimethylnic- otinic acid:
[1162] 5 ml of acetone was added to 132 mg (0.21 mmol) of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic
acid mono (3-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene)
piperidine-1-yl) propan-1-yl) ester. 233 mg (0.43 mmol) of cerium
ammonium nitrate suspended in 5 ml of water was added and stirred
at room temperature for 2 hours. After acetone was evaporated under
reduced pressure, ethyl acetate was added and precipitates were
taken by the filtration and dried under reduced pressure to obtain
the title compound.
[1163] Yield: 130 mg (0.21 mmol) (100%)
[1164] MS (ESI, m/z) 619 (M+H).sup.+
[1165] 1H-NMR (CDCl3): 1.64-2.72 (10H, m), 2.53 (3H, s), 2.59 (3H,
s), 3.19-3.34 (2H, m), 3.82-4.01 (2H, m), 6.92 (2H, s), 7.08-7.40
(12H, m).
EXAMPLE 152
[1166] Synthesis of
4-(3-chlorophenyl)-2,6-di(methyl-5-(4-methylpiperazine-
-1-carbonyl)nicotinic acid (2-(5H-dibenzo[a,d] cyclohepten-5-yl)
ethyl) ester:
[1167] 1) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
-3,5-dicarboxylic acid mono 3-(2-cyanoethyl) ester
5-(2-(5H-dibenzo[a,d] cyclohepten-5-yl) ethyl) ester:
[1168] 472 mg (2.0 mmol) of 1-(5H-dibenzo[a,d] cyclohepten-5-yl)
ethanol, 0.03 ml (0.2 mmol) of triethylamine and 0.345 ml (4.47
mmol) of diketene were heated and stirred in 10 ml of toluene at
80.degree. C. for 3.5 hours. After saturated aqueous sodium
hydrogencarbonate solution was added at room temperature, the
reaction mixture was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. 20 ml of 2-propanol, 312 mg
(2.02 mmol) of 3-aminocrotonate 2-cyanoethyl and 0.23 ml (2.03
mmol) of 3-chlorobenzaldehyde were added to the residue and the
residue was heated and stirred at 80.degree. C. overnight. After
evaporating 2-propanol under reduced pressure, saturated aqueous
sodium chloride solution was added and the reaction mixture was
extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by the basic silica gel
chromatography (hexane/ethyl acetate=9/1 to 1/3) to obtain the
title compound.
[1169] Yield: 153 mg (0.27 mmol) (13%)
[1170] MS (ESI, m/z) 577 (M-H).sup.-
[1171] 1H-NMR (CDCl3): 1.97-2.07 (2H, m), 2.35 (6H, s), 2.67 (2H,
t), 3.68 (2H, t), 3.98 (1H, t), 4.24-4.40 (2H, m), 5.03 (1H, s),
5.76 (1H, s), 6.88 (2H, s), 6.90-6.93 (1H, m), 7.10-7.34 (11H,
m).
[1172] 2) Synthesis of
4-(3-chlorophenyl)-2,6-dimethyl-5-(4-methylpiperazi-
ne-1-carbonyl)nicotinic acid (2-(5H-dibenzo[a,d] cyclohepten-5-yl)
ethyl) ester:
[1173] 4 ml of methanol and 0.32 ml of 1 N aqueous sodium hydroxide
solution were added to 153 mg (0.265 mmol) of
4-(3-chlorophenyl)-2,6-dime-
thyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-(2-cyanoethyl)
ester 5-(2-(5H-dibenzo[a,d] cyclohepten-5-yl) ethyl) ester and
stirred at room temperature overnight. After adding 1 N
hydrochloric acid, methanol was evaporated under reduced pressure.
After water was added, the reaction mixture was extracted with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. 5 ml of
dichloromethane, 68 mg (0.352 mmol) of WSC hydrochloride, 0.039 ml
(0.352 mmol) of N-methylpiperazine, 0.049 ml (0.352 mmol) of
triethylamine and 3.6 mg (0.029 mmol) of dimethylaminopyridine were
added to the residue and the residue was stirred at room
temperature overnight. 2 ml of trifluoroacetate was added and
stirred at room temperature for 4 hours. After concentration under
reduced pressure, saturated aqueous sodium hydrogencarbonate
solution was added to basify. After extraction with ethyl acetate,
the organic layer was dried over anhydrous sodium sulfate and then
concentrated under reduced pressure. The residue was purified by
the silica gel chromatography (dichloromethane/methanol=9/1) to
obtain the title compound.
[1174] Yield: 118 mg (0.194 mmol) (73%)
[1175] MS (ESI, m/z) 606 (M+H).sup.+
[1176] 1H-NMR (CDCl3): 1.73-1.84 (2H, m), 1.94-2.03 (1H, m),
2.10-2.18 (4H, m), 2.28-2.36 (1H, m), 2.53-2.58 (7H, m), 2.79-2.89
(1H, m), 3.04-3.11 (1H, m), 3.41-3.49 (1H, m), 3.55-3.64 (3H, m),
3.84 (1H, t), 6.86 (2H, s), 7.02-7.05 (1H, m), 7.10-7.15 (1H, m),
7.18-7.31 (10H, m).
[1177] The structural formulae of the compounds obtained in
Examples 1 to 152 are shown below.
1TABLE 1 Ex. Structure 1 31 2 32 3 33 4 34 5 35 6 36 7 37 8 38
[1178]
2TABLE 2 Ex. Structure 9 39 10 40 11 41 12 42 13 43 14 44 15 45 16
46
[1179]
3TABLE 3 Ex. Structure 17 47 18 48 19 49 20 50 21 51 22 52 23 53 24
54
[1180]
4TABLE 4 Ex. Structure 25 55 26 56 27 57 28 58 29 59 30 60 31 61 32
62
[1181]
5TABLE 5 Ex. Structure 33 63 34 64 35 65 36 66 37 67 38 68 39 69 40
70
[1182]
6TABLE 6 Ex. Structure 41 71 42 72 43 73 44 74 45 75 46 76 47 77 48
78
[1183]
7TABLE 7 Ex. Structure 49 79 50 80 51 81 52 82 53 83 54 84 55 85 56
86
[1184]
8TABLE 8 Ex. Structure 57 87 58 88 59 89 60 90 61 91 62 92 63 93 64
94
[1185]
9TABLE 9 Ex. Structure 65 95 66 96 67 97 68 98 69 99 70 100 71 101
72 102
[1186]
10TABLE 10 Ex. Structure 73 103 74 104 75 105 76 106 77 107 78 108
79 109 80 110
[1187]
11TABLE 11 Ex. Structure Ex. Structure 81 111 85 112 82 113 86 114
83 115 87 116 84 117 88 118
[1188]
12TABLE 12 Ex. Structure Ex. Structure 89 119 93 120 90 121 94 122
91 123 95 124 92 125 96 126
[1189]
13TABLE13 Ex. Structure Ex. Structure 97 127 101 128 98 129 102 130
99 131 103 132 100 133 104 134
[1190]
14TABLE 14 Ex. Structure Ex. Structure 105 135 109 136 106 137 110
138 107 139 111 140 108 141 112 142
[1191]
15TABLE 15 Ex. Structure Ex. Structure 113 143 117 144 114 145 118
146 115 147 119 148 116 149 120 150
[1192]
16TABLE 16 Ex. Structure Ex. Structure 121 151 125 152 122 153 126
154 123 155 127 156 124 157 128 158
[1193]
17TABLE 17 Ex. Structure Ex. Structure 129 159 133 160 130 161 134
162 131 163 135 164 132 165 136 166
[1194]
18TABLE 18 Ex. Structure Ex. Structure 137 167 141 168 138 169 142
170 139 171 143 172 140 173 144 174
[1195]
19TABLE 19 Ex. Structure Ex. Structure 145 175 149 176 146 177 150
178 147 179 151 180 148 181 152 182
[1196] (Test Example) Antagonistic Activity on N-Type Calcium
Channels (Fluorescence Dye Method):
[1197] Human neuroblastoma cells IMR-32 were obtained from ATCC
(American Type Culture Collection). The medium used was a phenol
red-free Eagle minimum essential medium containing earle's salts
(GIBCO) supplemented with 2 mM of L-glutamine (GIBCO), 1 mM of
sodium pyruvate (pH 6.5) (GIBCO), antibiotic/antimicotic mixture
(GIBCO) and 10% fetal calf serum (Cell Culture Technologies). Three
ml of 1.times.10.sup.5 cells /ml IMR-32 were spread on a 35 mm
diameter glass dish (Iwaki Glass Co., Ltd.) which was treated with
poly-L-lysin (SIGMA) and collagen (COLLAGEN VITROGEN 100, Collagen
Co.). One day after cultivation, 1 mM (final concentration) of
dibutyl cAMP and 2.5 .mu.M (final concentration) of
5-bromodeoxyuridine (SIGMA) were added. After the culture for
additional 10 to 14 days, the cells were subjected to the activity
determination.
[1198] The medium for IMR-32 cells thus prepared was replaced with
1 ml of Phenol Red-free Eagle minimum essential medium (GIBCO)
containing 2.5 .mu.M fura-2/AM (Dojin Kagaku, Co.) and earle's
salts supplement, and the incubation was conducted at 37.degree. C.
for 30 minutes. Then the medium was replaced with a recording
medium (20 mM of HEPES-KOH, 115 mM of NaCl, 5.4 mM of KCl, 0.8 mM
of MgCl.sub.2, 1.8 mM of CaCl.sub.2 and 13.8 mM of D-glucose).
Antagonistic activity on N-type calcium channels was determined and
analyzed using a fluorescence microscope (Nikon Corporation) and an
image analysis device ARGUS 50 (Hamamatsu Photonics). In
particular, a recording medium (20 mM of HEPES-KOH, 115 mM of NaCl,
5.4 mM of KCl, 0.8 mM of MgCl.sub.2, 1.8 mM of CaCl.sub.2 and 13.8
mM of D-glucose) containing 1 .mu.M of Nifedipine was given to the
cells by reflux by a Y-tube method for 2 minutes. Then a
stimulating agent containing 60 mM of potassium chloride was
rapidly given by the Y-tube method. The calcium concentration
change in the cells was examined in terms of N-type calcium channel
activity. Stimulating agents containing 60 mM of potassium chloride
and 0.1, 1 or 10 .mu.M of test compound were successively and
rapidly given to the same cells by the Y-tube method to determine
the change in calcium concentration in the cells on this occasion.
Antagonistic activity on N-type calcium channel was thus calculated
from the inhibition rates.
[1199] (Test Example) Antagonistic Activity on L-Type Calcium
Channels:
[1200] The activity of the dihydropyrimidine derivatives of the
present invention to inhibit L-type calcium channels was determined
by the following method in which the relaxation reaction on the
KCl-induced contraction of isolated rat thoracic aorta was
employed.
[1201] 1) Method of Preparation of Rat Thoracic Aorta:
[1202] The thoracic aorta isolated from a Wistar rat was cut to
obtain ring-shaped samples having a width of about 3 mm. The
endothelial cells of the samples were mechanically removed. The
samples were then suspended in a strain gage in Tyrode's solution
(158.3 mM of NaCl, 4.0 mM of KCl, 1.05 mM of MgCl.sub.2, 0.42 mM of
NaH.sub.2PO.sub.4, 10 mM of NaHCO, 2 mM of CaCl.sub.2 and 5 mM of
glucose) in which a gaseous mixture of O.sub.2 (95%) and CO.sub.2
(5%) was introduced. A static tension of 2 g was applied hereto.
The tension of the blood vessel was amplified with a transducer and
a tension amplifier (EF-601G; Nihon Koden Corporation) and recorded
with a multi-pen recorder (Rikadenki Kogyo Co., Ltd.). The
experiments were conducted at 37.degree. C.
[1203] 2) Measurment of Relaxation Response Against KCl-Induced
Contraction:
[1204] After the tension had been stabilized, the solution in the
sample tank was replaced with High K.sup.+ Tyrode's solution (112.3
mM of NaCl, 50 mM of KCl, 1.05 mM of MgCl.sub.2, 0.42 mM of
NaH.sub.2PO.sub.4, 10 mM of NaHCO.sub.3, 2 mM of CaCl.sub.2 and 5
mM of glucose) to conduct the contraction reaction. Thirty minutes
after, the solution in the sample tank was replaced with the normal
Tyrode's solution. The solution in the sample tank was again
replaced with the High K.sup.+ Tyrode's solution and the
contraction reaction was observed. After attaining the maximum
contraction reaction, the test compound was cumulatively added at
intervals of 90 minutes to attain concentrations of 10.sup.-9,
10.sup.-8, 10.sup.-7 and 10.sup.-6 M. The inhibitory rate of the
test compound on the maximum contraction reaction was employed as
the index of the inhibition activity on L-type calcium
channels.
[1205] Table 20 shows the results of the determination of the
antagonistic activity against the N-type calcium channels (pIC50)
and the L-type calcium channels (pIC50). The value of pIC50
indicates the antagonistic activity of the test compound Showing a
negative logarithm of the concentration of a test compound
necessitated for 50% inhibition.
20TABLE 20 N-type inhibition L-type inhibition Example pIC50 pIC50
1 5.8 5.6 16 5.7 5.5 122 5.8 6.0
[1206] The same procedure as that of the above-described tests of
the N-type calcium channel antagonistic activity of the compounds
obtained in the Examples was repeated except for the following
changes: stimulating agents containing 60 mM of potassium chloride
and 0.1, 1 or 10 .mu.M of test compound were successively and
rapidly given by the Y-tube method. A change in calcium
concentration in the cells was determined. N-type calcium channel
antagonistic activities calculated from the inhibition rates (%) at
10 .mu.M are shown in Table 21.
21TABLE 21 N-type inhibition L-type inhibition Example (inhibition
rate (%) at 10 .mu.M) pIC50 1 52% 5.6 16 58% 5.5 93 63% 5.3 103 74%
5.4 110 77% 5.6 122 56% 6.0 125 70% 5.9
[1207] (Test Example) Determination of Analgesic Action (Analgesic
Action in the Formalin Test)
[1208] 1) Preparation of Solution of a Test Compound and its
Administration
[1209] The compound was weighed and ground in a mortar. While
grinding the powder, 0.5% tragacanth solution was added thereto so
that a suspension was prepared to have a concentration of 0.6
mg/ml.
[1210] Three hours before the formalin injection, the compound
suspension was orally administered to SD rats at a volume of 5
ml/kg (dosage; 3 mg/kg, p.o.). In the control group, 0.5%
tragacanth solution was orally administered to SD rats at a volume
of 5 ml/kg 3 hours before formalin injection.
[1211] 2) Determination of Analgesic Action in the Formalin
Test
[1212] The SD rats to which the compound was administered were
introduced to a capsule. They were settled under halothane (2 to 4%
in 3 L/min of oxigen gas flow rate) and 100 .mu.l of 5% formalin
solution was injected subcutaneously to their dorsal surface of
left legs. After injection, determination was started when the rats
came out from the anesthetic state (based on recovery of righting
reflex). The number of flinching under the influence of formalin
injection was counted for 60 minutes (Reference: J. Neurosci. 14:
4882-4890 (1994)). The results are shown as "average.+-.standard
error" in Table 22.
22 TABLE 22 Flinching Example (number) Control group 116 .+-. 8 93
39 .+-. 11 122 61 .+-. 16 125 62 .+-. 25
[1213] As is apparent from the results above, the new pyrimidine
and pyridine derivatives have excellent selective N-type calcium
channel antagonistic activity and that they are useful as a
therapeutic agent for pains and various diseases associated with
the N-type calcium channels.
[1214] The new pyrimidine and pyridine derivatives of the present
invention had selective N-type calcium channel antagonistic
activity. Thus, the new dihydropyrimidine derivatives of the
present invention are effective in the treatment of acute stage of
ischemic cerebrovascular disorders such as cerebral infarction or
intracerebral bleeding (including subarachnoidal hemorrhage);
progressive neurodegenerative diseases such as Alzheimer's disease,
AIDS related dementia, Parkinson's disease, dementia due to
cerebrovascular disorder and ALS; cerebral disorders caused by head
injury; pains and cold flush caused by diabetes or thromboangiitis
obliterans; various pains such as neuropathic pain, migraine,
visceral pain and cancer pain; bronchial asthma; various diseases
associated with psychogenic stress such as unstable angina and
irritable colitis; withdrawal symptoms after addiction to drugs
such as emotional disorder and ethanol withdrawal symptoms.
* * * * *